CN116239566A - E3 ubiquitin ligase ligand compound, protein degradation agent developed based on ligand compound and application thereof - Google Patents
E3 ubiquitin ligase ligand compound, protein degradation agent developed based on ligand compound and application thereof Download PDFInfo
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- CN116239566A CN116239566A CN202211638397.8A CN202211638397A CN116239566A CN 116239566 A CN116239566 A CN 116239566A CN 202211638397 A CN202211638397 A CN 202211638397A CN 116239566 A CN116239566 A CN 116239566A
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- dione
- oxoisoindolin
- amino
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- 239000004480 active ingredient Substances 0.000 claims abstract 3
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Abstract
The present disclosure relates to compounds of formula (I) and formula (II) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogues, prodrugs or polymorphs thereof and uses thereof. The present disclosure also relates to pharmaceutical compositions comprising as an active ingredient a compound of formula (I) and formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof, and uses thereof.
Description
Technical Field
The present disclosure relates to cerebellar protein (CRBN) E3 ubiquitin ligase ligand compounds of formula (I), protein degrading compounds of formula (II) comprising the same, and uses thereof. CRBN E3 ubiquitin ligase ligand compounds are useful for treating or preventing a disease or condition mediated by the cereblon protein. The protein degrading compounds of formula (II) are effective in treating or preventing diseases or conditions associated with the degraded protein.
Background
The bi-functional protein degradation targeting drug consists of three parts, one end of which is a ligand warhead capable of combining with specific target protein, and the other end of which is a small molecule ligand of E3 ubiquitin ligase, and the two parts are connected by a linking unit with different lengths and types in the middle. The bifunctional protein-degrading small molecule compound can simultaneously bind a specific target protein and E3 ubiquitin ligase by utilizing the binding action of ligands at both ends, thereby recruiting the E3 ubiquitin ligase to the vicinity of the specific target protein and enabling the E3 ubiquitin ligase to ubiquitously label the target protein. The target protein labeled by multiple ubiquitination is recognized and degraded by the proteasome in vivo. Compared with the traditional inhibitor small molecule drugs, the biggest difference of the protein degradation targeting drugs is that the whole cells are mobilized as drug effect units. The drug action mode only needs to combine small molecular drugs with target proteins transiently, and the target proteins are marked with the label of 'need to be cleaned', so that the low-concentration drug dosage can meet the requirement, the risk of off-target effect is greatly reduced, and the tumor progress caused by abnormal expression of driving genes and the drug resistance caused by acquired mutation of the driving genes can be fundamentally eliminated.
The E3 ubiquitin ligases involved in the design of protein degradation targeted drugs comprise more than 500 different proteins, each with a different cellular expression profile, and can be classified into several classes according to the structural elements of their E3 functional activity. Currently, only a few ligases are successfully used in the study of preclinical degradants, cereblon (CRBN) E3 ubiquitin ligase is one of the most widely used E3 ubiquitin ligases. Currently known E3 ubiquitin ligase ligands of the CRBN type (CRBN ligands) include thalidomide and its analogues pomalidomide and lenalidomide, all of which have a phthalimide backbone. The CRBN type E3 ubiquitin ligase ligand itself may also be used as a molecular gel to induce degradation of specific proteins. Cereblon (CRBN) forms a functional E3 ubiquitin ligase complex with impaired DNA binding protein 1 (DDB 1) and Cullin 4A, in which complex CRBN acts as a substrate receptor and molecular gelatin degrading agents such as thalidomide, when combined with CRBN, induce the CRBN to recognize new substrate proteins which are ubiquitinated and further recognized by proteasome for degradation.
CRBN ligands have been widely used for protein degradation and a series of small molecules based on CRBN ligands have been developed that exploit the function of the CRBN E3 ubiquitin ligase complex. Because CRBN ligand can be used as a molecular gel degradation agent to induce different substrate proteins to degrade, can be used as a part of a bi-functional protein degradation drug to realize effective degradation of specific pathogenic proteins, and meanwhile, the existing multi-degree amine compound has unavoidable side effects and drug resistance problems, the novel and optimized E3 ubiquitination ligase ligand is designed, the research on the binding capacity and biological activity of the ligand with CRBN is of great significance, and the ligand can be further applied to bi-functional protein degradation small-molecule drugs.
Thus, there is an urgent need for a series of novel CRBN E3 ubiquitin ligase ligands that can act as potent molecular gel degrading agents, and that can further synthesize corresponding bifunctional protein degrading agents for the treatment and/or prevention of diseases or conditions mediated by or associated with degraded proteins.
Summary of The Invention
In view of the above, it is an object of the present disclosure to provide novel CRBN E3 ubiquitin ligase ligands, protein degrading molecules designed based on novel CRBN E3 ubiquitin ligase ligands and various target protein ligands, their uses, and methods of their use. The compounds provided herein are advantageous in that they can possess a broad range of pharmacological activities through degradation/inhibition of a variety of different pathogenic protein classes or families.
To achieve the above and other related objects, in one aspect, the present disclosure provides novel CRBN E3 ubiquitin ligase ligands which may themselves act as molecular binders to CRBN E3 ligases and thereby induce degradation of CRBN substrate proteins including, but not limited to GSPT1, IKZF2, IKZF3 (Aiolos) and IKZF4 proteins.
In some embodiments, the novel CRBN E3 ubiquitin ligase ligand of the present disclosure may be a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof:
Wherein the method comprises the steps of
A represents CO or CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents, for example, hydrogen, deuterium, halogen, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, or halo C 1-6 An alkyl group;
(R a ) m represents that the benzene ring is substituted by m R a Substituted, each R a The structural formulae are the following, which are identical or different and each independently of the others:
wherein,,
r represents chlorine, bromine, iodine, hydroxyl, leaving group, NR 7 R 8 Or a group W 1 ，
Wherein R is 7 And R is 8 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, C 2-6 alkynyl-C 1-6 Alkylene-, C 2-6 alkenyl-C 1-6 Alkylene-, optionally substituted 4-to 15-membered nitrogen containing heterocyclyl, or R 2a -R 1a -, wherein R is 1a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 2a Represents halogen, amino, hydroxy, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl or leaving group; and
group W 1 The structure of the following formula is shown:
wherein ring W 2 Represents optionally substituted nitrogen-containing heterocyclic groups, each ring W 3 Identical or different and each independently represents an optionally substituted nitrogen-containing heterocyclic group, t represents an integer 1 or 2, and ring W 4 Represents an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl;
R 5 and R is 6 Identical or different and each independently represents hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、
OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl group,
NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
Or (b)
R and R 5 Together with the carbon atom to which they are attached form a carbonyl group, R 6 Represents hydrogen, optionally substituted methyl, or optionally substituted straight or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、
OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -
C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-or any of
A substituent group intended to be combined;
(R b ) n represents the benzene ring is substituted by n R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; and
m represents an integer 1, 2, 3 or 4, n represents an integer 0, 1, 2 or 3, and the sum of m and n is an integer 1, 2, 3 or 4; wherein when R and R 5 Together with the carbon atom to which they are attached form a carbonyl group and R 6 When representing hydrogen, m represents an integer 1, 2 or 3, n represents an integer 1, 2 or 3, and the sum of m and n is an integer 2, 3 or 4;
with the proviso that the following compounds and compounds of formula (I') are excluded:
When A represents CH 2 Or C (O), and R represents an unhooked oneIn the case of substituted piperazinyl groups, m represents an integer 1 and n represents an integer 0;
when A represents CH 2 Or C (O), and R a Represents H 2 N-CH 2 -when m represents an integer 1 and n represents an integer 0;
when a represents C (O), and R represents bromine, m represents an integer 1 and n represents an integer 0; and
wherein in formula (I'), A represents CH 2 Or C (O), and R represents unsubstituted piperidinyl or piperidinyl substituted with methylamino.
In another aspect, the proteolytic molecule of the present disclosure is a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof:
PBM-R f -LIN-ULM
formula (II)
Wherein PBM-R f -representing a targeting moiety capable of binding to a protein, ULM representing a ligand moiety capable of binding to E3 ubiquitin ligase, LIN being a linking moiety, PBM-R f -covalently linking ULM through the group LIN;
ULM represents the structure of the following formula (ULM):
wherein the method comprises the steps of
A represents CO or CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, or halo C 1-6 An alkyl group;
(R b ) n represents the benzene ring optionally substituted by n R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitroRadical, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl;
n represents an integer of 0, 1, 2 or 3;
LIN represents the structure of the formula:
wherein R is 5 And R is 6 Identical or different and each independently represents hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C 1-6 Alkoxy, optionally deuteratedC of (2) 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
R f Represents a bond, -O-, -N (R) g )-、-NHC(O)-R h -W 5 -*、-C(O)NH-R h -W 5 -*、-NHC(O)-W 5 -*、-C(O)NH-W 5 -*、-NHC(O)-*、-C(O)NH-*、-O-R h -W 5 -*、-O-W 5 -*、-O-R h -N(R i )-*、-N(R g )-R h -N(R i )-*、-W 5 -、-W 5 -N(R g )-*、-N(R g )-W 5 -*、-N(R g )-W 5 -N(R i )-*、-R h -W 5 -*、-R h -C(O)-W 5 -*、-C(O)-W 5 -*、-R h -C(O)NH-R j -W 5 -*、-R h -NHC(O)-R j -W 5 -*、-R h -C(O)NH-*、-R h -NHC(O)-*、-R h -、-R h -N(R i ) -, or
Wherein the radical W 5 The structure of the following formula is shown:
wherein each ring W 6 Identical or different and each independently represents a nitrogen-containing heterocyclylene group, t1 represents an integer 1 or 2, (R) a2 ) m2
Representing each ring W 6 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6
Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m2 represents an integer of 0 to 20;
each ring W 7 Identical or different and each independently represents a nitrogen-containing heterocyclylene, arylene, or heteroarylene group, t2 represents an integer 0 or 1, (R) a3 ) m3 Representing each ring W 7 Independently optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl group,
C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein
R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m3 represents an integer of 0 to 20; and
R g and R is i Each independently represents hydrogen or C 1-6 Alkyl, R h And R is j Each independently represents optionally substituted C 1-6 Alkylene group
C being optionally substituted or substituted 2-6 Alkenylene, and the symbol represents the point of attachment to LIN;
wherein, when PBM represents the following structural formula:
and at the same time-R f -LIN-representation
Wherein the symbols denote the points of attachment to the ULM, (R) b ) n The benzene ring of formula (ULM) is substituted with 1, 2 or 3R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl;
provided that the following compounds were excluded:
3- (4- ((3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) pyrrolidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) azetidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione; and
2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) azetidin-1-yl) methyl) isoindoline-1, 3-dione.
In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof, and at least one pharmaceutically acceptable carrier.
In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof, and at least one pharmaceutically acceptable carrier.
In another aspect, the present disclosure also provides a kit or kit comprising:
a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same; or (b)
A compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
In another aspect, the present disclosure provides a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, or a pharmaceutical composition comprising the same as an active ingredient, for use as a medicament.
In another aspect, the present disclosure further provides a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, or a pharmaceutical composition comprising the same as an active ingredient, for use in the treatment or prevention of a cereblon protein-mediated disease or disorder.
In some embodiments, the cereblon protein-mediated disease or disorder includes, but is not limited to, a tumor, an infectious disease, an auto-inflammatory disease, an autoimmune disease, a neurological disease, a respiratory disease, anemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular disease, weng Weili-his syndrome, richter Syndrome (RS), acute liver failure, or diabetes.
In another aspect, the present disclosure provides a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, or a pharmaceutical composition comprising the same as an active ingredient, for use as a medicament.
In another aspect, the present disclosure further provides a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof or a pharmaceutical composition comprising the same as an active ingredient for use in the treatment and/or prevention of a disease or disorder selected from the group consisting of: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, weng Weili Hirsh syndrome, richter Syndrome (RS), acute liver failure, diabetes, kennedy disease, seborrheic alopecia, hirsutism, skin diseases, cardiovascular diseases, dysfunctional uterine bleeding, anaemia, pediatric aplastic anemia, endometriosis, transplant rejection, polycystic ovary syndrome, or thyroid diseases.
In another aspect, the present disclosure provides the use of a compound of formula (I) or a salt, enantiomer, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof, for preparing a compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof of the present disclosure.
In another aspect, the present disclosure also provides methods of preparing a compound of formula (II) of the present disclosure, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof, using the compound of formula (I), or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof.
In another aspect, the present disclosure also provides the use of a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, for the preparation of a medicament for the treatment or prophylaxis of a disease or condition mediated by the cereblon protein.
In another aspect, the present disclosure also provides the use of a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof, for the preparation of a medicament for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, weng Weili Hirsh syndrome, richter Syndrome (RS), acute liver failure, diabetes, kennedy disease, seborrheic alopecia, hirsutism, skin diseases, cardiovascular diseases, dysfunctional uterine bleeding, anaemia, pediatric aplastic anemia, endometriosis, transplant rejection, polycystic ovary syndrome, or thyroid diseases.
In another aspect, the present disclosure also provides a method of treating or preventing a cereblon protein-mediated disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof, or a pharmaceutical composition comprising the same.
In another aspect, the present disclosure also provides a method of treating or preventing a disease or disorder in a subject, wherein the disease or disorder comprises a tumor, an infectious disease, an autoinflammatory disease, an inflammatory disease, an autoimmune disease, a neurological disease, a respiratory disease, anemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, weng Weili hilt syndrome (Unverricht Syndrome), richter Syndrome (RS), acute liver failure, diabetes, kennedy disease (Kennedy disease), seborrheic alopecia, hirsutism, skin disease, cardiovascular disease, functional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, transplant rejection, polycystic ovary syndrome, and thyroid disease, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (II), or a salt, enantiomer, stereoisomer, solvate, enriched analog, prodrug, or polymorph thereof.
Detailed Description
The following detailed description is provided as an exemplary embodiment to assist those of ordinary skill in the art in understanding and practicing the present disclosure. It will be appreciated, however, that such description is not intended to limit the scope of the present disclosure, and that various modifications and changes may be made to the particular embodiments described in the present disclosure without departing from the spirit and scope of the present disclosure, which changes and modifications fall within the scope of the present disclosure as claimed.
I. Compounds of formula (I)
A compound of formula (I)
The present disclosure provides a compound of formula (I) or a salt (including pharmaceutically acceptable salts), stereoisomer (including enantiomers), solvate, isotopically enriched analog, prodrug, or polymorph thereof:
therein A, R 1 、R 2 、R 3 、R 4 、(R a ) m 、(R b ) n M and n are as defined above for the compounds of formula (I).
In some embodiments, R of the compound of formula (I) 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R of the compound of formula (I) 1 、R 2 、R 3 And R is 4 The same or different and each independently represents hydrogen or deuterium.
In some embodiments, R of the compound of formula (I) 1 、R 2 、R 3 And R is 4 Represents hydrogen.
In some embodiments, a of the compound of formula (I) represents CO.
In some embodiments, A of the compound of formula (I) represents CH 2 。
In some embodiments, A of the compound of formula (I) represents CD 2 。
In some embodiments, m of the compound of formula (I) represents an integer of 1, n represents an integer of 0, 1, 2, or 3, and the sum of m and n is an integer of 1, 2, 3, or 4.
In some embodiments, m of the compound of formula (I) represents an integer of 2, n represents an integer of 0, 1 or 2, and the sum of m and n is an integer of 2, 3 or 4.
In some embodiments, when R and R 5 Together with the carbon atom to which they are attached form a carbonyl group and R 6 When hydrogen is represented, m represents an integer 1, 2 or 3, n represents an integer 1, 2 or 3, and the sum of m and n is an integer 2, 3 or 4. In some sub-embodiments, m represents an integer 1, n represents an integer 1, 2, or 3, and the sum of m and n is an integer 2, 3, or 4. In some sub-embodiments, m represents an integer 2, n represents an integer 1 or 2, and the sum of m and n is an integer 3 or 4. In some sub-embodiments, m represents an integer 3 and n represents an integer 1.
In some embodiments, R of the compound of formula (I) represents chloro, bromo, iodo, hydroxy or a leaving group (e.g., -N 3 Chlorine, bromine, iodine, sulfonate groups, such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyl oxy (TfO-), or p-toluenesulfonyloxy (TsO-).
In some embodiments, R of the compound of formula (I) represents NR 7 R 8 Wherein R is 7 And R is 8 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 2-6 alkynyl-C 1-6 Alkylene- (e.g. C) 2-6 alkynyl-C 1-4 Alkylene-or C 2-6 alkynyl-C 1-3 Alkylene-, e.g. ethynyl-methylene-, ethynyl-ethylene-, ethynyl-propylene-, ethynyl-butylene-, ethynyl-pentylene-, or ethynyl-hexylene-), C 2-6 alkenyl-C 1-6 Alkylene- (e.g. C) 2-6 alkenyl-C 1-4 Alkylene-or C 2-6 alkenyl-C 1-3 Alkylene-, e.g. vinyl-methylene-, vinyl-ethylene-, vinyl-propylene-, vinyl-butylene-, vinyl-pentylene-, or vinyl-hexylene-), optionally substituted 4-to 15-membered (e.g. 4-11 membered, 4-membered)A nitrogen-containing monocyclic heterocyclyl group of from 10 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 5 to 15, or 5 to 9, an optionally substituted 4-to 15-membered (e.g., 4-11, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 5 to 15, or 5 to 9) nitrogen-containing bridged heterocyclyl group, or an optionally substituted 4-to 15-membered (e.g., 4-11, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 5 to 15, or 5 to 9) nitrogen-containing spiro heterocyclyl group, or R 2a -R 1a -, wherein R is 1a Represents optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 2a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxyl, carboxyl, CHO, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl, or leaving groups (e.g. -N) 3 Chlorine, bromine, iodine, sulfonate groups, such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyl oxy (TfO-) or p-toluenesulfonyloxy (TsO-), the 4-to 15-membered nitrogen-containing monocyclic heterocyclyl, the 4-to 15-membered nitrogen-containing bridged heterocyclyl and the 4-to 15-membered nitrogen-containing spiro heterocyclyl each independently being optionally substituted with one or more (e.g., 1-10, such as 1, 2, 3, 4, 5, 6, 8, or 10) substituents selected from: deuterium, C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, tert-butyloxy, pentoxy, or hexyloxy), halogen (e.g. fluoro, chloro, bromo or iodo), leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-), amino, hydroxy, carboxylRadical, CHO, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl, e.g. ethenyl, propenyl, or butenyl), R 4a -R 3a -, or any combination thereof, wherein R 3a Represents optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 4a Represents halogen, R 5a R 6a N-, hydroxy, carboxy, CHO, ethynyl, vinyl, or a leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-)), wherein R 5a And R is 6a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl). The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block. For example, when the substituent is deuterium, each of the 4-to 15-membered nitrogen-containing monocyclic heterocyclic group, the 4-to 15-membered nitrogen-containing bridged heterocyclic group, and the 4-to 15-membered nitrogen-containing spiro heterocyclic group is independently optionally perdeuterated or partially deuterated.
In some sub-embodiments, R of the compound of formula (I) represents NR 7 R 8 Wherein R is 7 And R is 8 Identical or different and each independently represents:
hydrogen, C 1-6 Alkyl, C 2-6 alkynyl-C 1-6 Alkylene-, or C 2-6 alkenyl-C 1-6 An alkylene group; or (b)
Optionally substituted 4-to 15-membered nitrogen-containing monocyclic heterocyclyl, optionally substituted 4-to 15-membered nitrogen-containing bridged heterocyclyl, or optionally substituted 4-to 15-membered nitrogen-containing spiro heterocyclyl, e.g.,
piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazacycloheptyl, azacyclooctyl, diazacyclooctyl, azabicyclo [3.1.1] heptanyl, azabicyclo [2.2.1] heptanyl, azabicyclo [3.2.1] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [3.1.1] heptanyl, diazabicyclo [2.2.1] heptanyl, diazabicyclo [3.2.1] octanyl, diazabicyclo [2.2.2] octanyl, 3-azaspiro [5.5] undec-3-yl, 8-azaspiro [4.5] decane-4-yl, 2-oxa-8-azaspiro [4.5] decane-4-yl, or 3-methyl-2-oxa-8-azaspiro [4.5] decane-4-yl
R 2a -R 1a -, wherein R is 1a Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 2a Represents halogen, amino, hydroxy, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl or leaving group
Wherein each of said 4-to 15-membered nitrogen containing monocyclic heterocyclyl, said 4-to 15-membered nitrogen containing bridged heterocyclyl and said 4-to 15-membered nitrogen containing spiro heterocyclyl is optionally substituted with one or more (e.g., 1-10, such as 1, 2, 3, 4, 5, 6, 8, or 10) substituents selected from the group consisting of: deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, R 4a -R 3a -, or any combination thereof, wherein R 3a Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 4a Represents halogen, R 5a R 6a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 5a And R is 6a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group. The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block. For example, when the substituent is deuterium, the 4-to 15-membered nitrogen-containing monocyclic heterocyclic group, the 4-to 15-membered nitrogen-containing bridged heterocyclic group and the 4-to 15-membered nitrogen-containing spiro heterocyclic group are each independently Optionally fully deuterated or partially deuterated.
In some embodiments, R of the compound of formula (I) represents NH 2 、-NHCH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 、-N(CH 3 )-CH 2 CH 3 、-N(CH 3 )-CH 2 CH 2 Br、
In some embodiments, R of the compound of formula (I) represents a group W 1 Which is represented by the structure of the formula:
wherein ring W 2 Represents a 4-to 20-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) nitrogen-containing heterocyclic group, for example, a 4-to 20-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) heterocyclic group containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen, and sulfur,
(R a1 ) m1 representing ring W 2 Optionally by m 1R a1 Substituted by radicals, each R a1 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogen (e.g. fluorine, chlorine, bromine or iodine), leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-), amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 8a -R 7a -, wherein R is 7a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 8a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 9a R 10a N-, hydroxy, carboxy, CHO, ethynyl, vinyl, or a leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-)), wherein R 9a And R is 10a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl);
wherein m1 represents an integer of 0 to 20 (e.g., an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20). The number is in principle not limited by any restrictions or by the size of the building elements.
In some sub-embodiments, R of the compound of formula (I) represents a group W 1 Which is represented by the structure of the formula:
wherein ring W 2 Represents a 4-to 20-membered nitrogen-containing heterocyclic group, for example, a 4-to 20-membered (for example, 4-to 15-membered, 4-to 12-membered, 4-to 11-membered, 4-to 10-membered, 4-to 9-membered, 4-to 8-membered, 4-to 7-membered, 4-to 6-membered, 5-to 15-membered, or 5-to 9-membered) heterocyclic group containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen and sulfur, for example,
piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazepinyl, azetidinyl, diazacyclooctyl, azabicyclo [3.1.1] heptanyl, azabicyclo [2.2.1] heptanyl, azabicyclo [3.2.1] octanyl, azabicyclo
[2.2.2] octyl, diazabicyclo [3.1.1] heptyl, diazabicyclo [2.2.1] heptyl, and diazabicyclo
[3.2.1] octyl, diazabicyclo [2.2.2] octyl, 3-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decyl, 2-oxa-8-azaspiro [4.5] decyl, or 3-methyl-2-oxa-8-azaspiro [4.5] decyl
(R a1 ) m1 Representing ring W 2 Optionally by m 1R a1 Substituted by radicals, each R a1 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 8a -R 7a -, wherein R is 7a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 8a Represents halogen, R 9a R 10a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 9a And R is 10a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group;
wherein m1 represents an integer of 0 to 20 (e.g., an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20). The number is in principle not limited by any restrictions or by the size of the building elements.
In some embodiments, ring W 2 Optionally fully deuterated or partially deuterated.
In some embodiments, R of the compound of formula (I) represents a group W 1 Which is represented by the structure of the formula:
wherein each ring W 3 The same or different and each independently represents a 4-to 20-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) nitrogen-containing heterocyclic group, for example, a 4-to 20-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) heterocyclic group containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen, and sulfur;
t represents an integer of 1 or 2, (R) a2 ) m2 Representing each ring W 3 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, tert-butyloxy, pentoxy, or hexyloxy), halogen (e.g. fluoro, chloro, bromo or iodo), leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-), amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (example)Such as optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 12a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 13a R 14a N-, hydroxy, carboxy, CHO, ethynyl, vinyl, or a leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-)), wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl); and
ring W 4 Represents a 4-to 15-membered (e.g., 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) nitrogen-containing heterocyclyl (e.g., a 4-to 15-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) heteroaryl group (e.g., a 5-to 10-membered (e.g., 5-to 9-, 5-to 8-, 5-to 7-, or 5-to 6-membered) heteroaryl group containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen, and sulfur);
(R a3 ) m3 Representing ring W 4 Optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, ethoxy, propoxy, isopropoxyA group, a butoxy group, a sec-butyloxy group, a tert-butyloxy group, a pentoxy group, or a hexoxy group), a halogen (e.g., fluorine, chlorine, bromine, or iodine), a leaving group (e.g., -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-), amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 16a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 17a R 18a N-, hydroxy, carboxy, CHO, ethynyl, vinyl, or a leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-)), wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl);
wherein m2, m3 each independently represent an integer of 0-20 (e.g., the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20). The number is in principle not limited by any restrictions or by the size of the building elements.
In some sub-embodiments, R of the compound of formula (I) represents a group W 1 Which is represented by the structure of the formula:
wherein each ring W 3 Identical or different and each independently represents a 4-to 20-membered nitrogen-containing heterocyclylene group, for example,
piperidylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene, diazepanylene, azepanylene, azetidinylene, diazepanylene, azabicyclo [3.1.1] heptanylene, azabicyclo [2.2.1] heptanylene, azabicyclo [2.2.2] octanylene, diazabicyclo [3.1.1] heptanylene
[2.2.1] Heptane subunit, diazabicyclo [3.2.1] octane subunit, diazabicyclo [2.2.2] octane subunit, 3-azaspiro [5.5]
Undecane subunit, 8-azaspiro [4.5] decane subunit, 2-oxa-8-azaspiro [4.5] decane subunit, or 3-methyl-2-oxa-8-azaspiro [4.5] decane subunit, or
t represents an integer of 1 or 2, (R) a2 ) m2 Representing each ring W 3 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; and
ring W 4 Represents 4-to 15-membered nitrogen-containing impuritiesA cyclic group, a 6-to 10-membered aryl group, or a 5-to 10-membered heteroaryl group, for example,
piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazepinyl, azetidinyl, diazacyclooctyl, azabicyclo [3.1.1] heptanyl, azabicyclo [2.2.1] heptanyl, azabicyclo [3.2.1] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [3.1.1] heptanyl, diazabicyclo [2.2.1] heptanyl, diazabicyclo [3.2.1] octanyl, diazabicyclo [2.2.2] octanyl, 3-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decanyl, 2-oxa-8-azaspiro [4.5]
Decyl, 3-methyl-2-oxa-8-azaspiro [4.5] decyl, phenyl, naphthyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2,1,3] oxadiazolyl, benzo [2,1,3] thiadiazolyl, benzo [1,2,3] thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrrolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2,3] pyrrolyl, imidazo [1, 3] pyrrolyl, 1, 2-b, 1-pyridyl, 1-3 ] pyrrolyl, 1-b, 1-pyridyl or 1-b-1, 3-imidazo [2, 3] pyrrolyl
(R a3 ) m3 Representing ring W 4 Optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, Carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group;
wherein m2, m3 each independently represent an integer of 0-20 (e.g., the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20). The number is in principle not limited by any restrictions or by the size of the building elements.
In some sub-embodiments, each ring W 3 Each independently optionally being fully deuterated or partially deuterated.
In some sub-embodiments, ring W 4 Optionally fully deuterated or partially deuterated.
In some sub-embodiments, R of the compound of formula (I) represents the following group:
chlorine, bromine, iodine, hydroxy, -N 3 Sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl (TfO-) or p-toluenesulfonyloxy (TsO-), NH 2 Or (b)
In some embodiments, R of the compound of formula (I) 5 And R is 6 Each independently represents:
hydrogen, fluorineChlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight or branched C 2-30 An alkyl group, a hydroxyl group,
wherein said straight or branched C 2-30 The main carbon chain of the alkyl group is optionally interrupted by one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R c And/or one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R d Or one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d To break carbon-carbon bonds between one or more pairs (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 pairs, or 1 pair) of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propylIsopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof; and
hydrogen of the methyl group and the C 2-30 One or more (e.g. 1-30, such as 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1) CH groups of alkyl groups 2 Optionally further substituted with a hydrogen selected fromBase substitution: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any combination thereof.
In some embodiments, R of the compound of formula (I) 5 Represents hydrogen, fluorine, chlorine, bromine,Iodine, optionally substituted methyl, optionally substituted methoxy, optionally substituted ethoxy, optionally substituted propoxy, optionally substituted butoxy, or optionally substituted tert-butoxy.
In some embodiments, R and R of the compound of formula (I) 5 Together with the carbon atoms to which they are attached form a carbonyl group. In other words, R of the compound of formula (I) a The following groups are represented:
wherein R is 6 As defined hereinabove.
In some embodiments, R and R 5 A compound of formula (I) as defined in any one of its embodiments and R 6 The representation is:
hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight or branched C 2-30 An alkyl group, a hydroxyl group,
wherein said straight or branched C 2-30 The main carbon chain of the alkyl group is optionally interrupted by one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R c And/or one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R d Or one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d To break carbon-carbon bonds between one or more pairs (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 pairs, or 1 pair) of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl group(e.g. C 1-4 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof; and
hydrogen of the methyl group and the C 2-30 One or more (e.g. 1-30, such as 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1) CH groups of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any combination thereof.
In some sub-embodiments, R of the compound of formula (I) 6 Represents hydrogen, fluorine, chlorine, bromine, or iodine.
In some sub-embodiments, R of the compound of formula (I) 6 The structure of the following formula is shown:
-C 1-30 an alkyl group;
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -(R c -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -(R d -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R c -R d -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -R c -(C(R a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
Wherein each group R c Selected from O, N (R) e )、C(O)、C(O)O、OC(O)、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 An alkyl group; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 5-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 5-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclyleneThe radicals and the heteroarylene radicals are, independently of one another, optionally further selected from deuterium, (e.g. optionally deuterated C) 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
the C is 1-30 One or more (e.g. 1-30, e.g. 1-2) alkyl groups5, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2 or 1) CH 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any ofA meaning combination;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -), or optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-); and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
In some sub-embodiments, R of the compound of formula (I) 6 The structure of the following formula is shown:
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(N(R e )-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(C(O)N(R e )-
(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -C(O)N(R e )-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)N(R e )-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 -C(O)-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 Arylene- (C (R) a8 )(R a9 )) n3 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heterocyclylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heteroarylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 - (cycloalkylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
Wherein each R e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
the cycloalkylene group (e.g. C 3-20 Cycloalkylene, C 3-15 Cycloalkylene, C 3-10 Cycloalkylene, C 3-8 Cycloalkylene, or C 3-6 Cycloalkylene), the arylene group (e.g. C 5-20 Arylene group, C 5-15 Arylene group, C 5-10 Arylene group, or C 5-6 Arylene), the heterocyclylene (e.g., 4-to 20-membered heterocyclylene, 4-to 15-membered heterocyclylene, 4-to 10-membered heterocyclylene, 4-to 9-membered heterocyclylene, 4-to 8-membered heterocyclylene, 5-to 7-membered heterocyclylene, or 6-membered heterocyclylene) and the heteroarylene (e.g., 5-to 20-membered heteroarylene, 5-to 15-membered heteroarylene, 5-to 10-membered heteroarylene, 5-to 9-membered heteroarylene, 5-to 8-membered heteroarylene, 5-to 7-membered heteroarylene, or 6-membered heteroarylene) independently of each other are optionally further substituted with a member selected from deuterium, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-,for example NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -), or optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-); and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
In some sub-embodiments, R of the compound of formula (I) 6 The following groups are represented:
H. fluorine, chlorine, bromine, iodine, -CH 3 、-CH 2 -CH 3 、-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -CH 3 、-(CH 2 ) 7 -CH 3 、-(CH 2 ) 8 -CH 3 、-(CH 2 ) 9 -CH 3 、-(CH 2 ) 10 -CH 3 、-(CH 2 ) 11 -CH 3 、-(CH 2 ) 12 -CH 3 、-(CH 2 ) 13 -CH 3 、-(CH 2 ) 14 -CH 3 、-(CH 2 ) 15 -CH 3 、-(CH 2 ) 16 -CH 3 、-(CH 2 ) 17 -CH 3 、-(CH 2 ) 18 -CH 3 、-(CH 2 ) 19 -CH 3 、-(CH 2 ) 20 -CH 3 、-(CH 2 ) 21 -CH 3 、-(CH 2 ) 22 -CH 3 、-(CH 2 ) 25 -CH 3 、-(CH 2 ) 29 -CH 3 ；-CH 2 -O-CH 3 、-CH 2 -O-CH 2 -CH 3 、-CH 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 11 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 12 -CH 3 、-(CH 2 ) 3 -O-CH 3 、-(CH 2 ) 3 -O-CH 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 4 -O-CH 3 、-(CH 2 ) 4 -O-CH 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 5 -O-CH 3 、-(CH 2 ) 5 -O-CH 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -O-CH 3 、-(CH 2 ) 6 -O-CH 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 7 -O-CH 3 、-(CH 2 ) 7 -O-CH 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 8 -O-CH 3 、-(CH 2 ) 8 -O-CH 2 -CH 3 、-(CH 2 ) 8 -O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-CH 3 、-CH(CH 3 )-O-CH 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 9 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 10 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 9 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 10 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 4 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 CH 3 、-(CH 2 ) 1 -N(R e )-CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 11 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 1 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 9 -CH 3 、-CH 2 C(O)NHCH 3 、-(CH 2 ) 2 C(O)NHCH 2 CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 C(O)NH(CH 2 ) 7 -CH 3 、U-(CH 2 ) 9 C(O)NH(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 C(O)NH(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -O-CH 2 -CH 3 、-CH 2 NHC(O)CH 3 、-(CH 2 ) 2 NHC(O)CH 2 CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 9 NHC(O)(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 NHC(O)(CH 2 ) 9 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 4 NHC(O)CH 3 、-CH 2 -piperidinyl-CH 3 、-CH 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperidinyl-CH 3 、-(CH 2 ) 3 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperidinyl-CH 3 、-(CH 2 ) 4 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperidinyl-CH 3 、-(CH 2 ) 5 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperidinyl-CH 3 、-(CH 2 ) 6 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperidinyl-CH 3 、-(CH 2 ) 7 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperidinyl-CH 3 、-(CH 2 ) 8 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -piperazinylene-CH 3 、-CH 2 -piperazinylene-CH 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperazinylene-CH 3 、-(CH 2 ) 2 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperazinylene-CH 3 、-(CH 2 ) 3 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperazinylene-CH 3 、-(CH 2 ) 4 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperazinylene-CH 3 、-(CH 2 ) 5 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperazinylene-CH 3 、-(CH 2 ) 6 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperazinylene-(CH 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperazinylene-CH 3 、-(CH 2 ) 7 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperazinylene-CH 3 、-(CH 2 ) 8 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 6 -CH 3 Or- (CH) 2 ) 8 -piperazinylene- (CH) 2 ) 7 -CH 3 ；
Wherein said piperidinyl and said piperazinyl independently of each other are optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-orCH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
CH in said group 3 For example, 1 to 30, for example, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) CH(s) 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl radicals [ (] C.For example optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any combination thereof;
each R is e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl); and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
In some embodiments, R of the compound of formula (I) 5 And R is 6 Represents hydrogen.
In some embodiments, (R) of the compound of formula (I) b ) n Represents the benzene ring is substituted by n R b Substituted, each R b Are identical or different and each independently represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, mercapto,Nitro, amino, cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy-, propoxy-, isopropoxy-, butoxy-, sec-butyloxy-or tert-butyloxy), halo-C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), C 2-6 Alkenyl (e.g. ethenyl, propenyl or butenyl), or C 2-6 Alkynyl (e.g., ethynyl, propynyl, or butynyl); wherein n represents an integer of 0, 1, 2, or 3. In some sub-embodiments, the optionally substituted C 3-6 The substituents of cycloalkyl groups being selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 alkyl-NH-, halo-C 1 -C 3 Alkyl, NH 2 -C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 The number of substituents may be one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) alkyl-C (O) NH-, cyano-, or any combination thereof. The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block.
In some embodiments, the compound of formula (I) is also a compound of formula (I-1) or formula (I-2):
therein A, R 1 、R 2 、R 3 、R 4 、(R b ) n And (R) a ) m A compound of formula (I) as defined above in the various embodiments.
In some embodiments, the compound of formula (I) is also a compound of formula (I-3) or formula (I-4):
wherein A, (R) b ) n And (R) a ) m A compound of formula (I) as defined above in the various embodiments.
In some embodiments, the compound of formula (I) is also a compound of formula (I-5), formula (I-6), formula (I-7), or formula (I-8) below:
therein A, R 1 、R 2 、R 3 、R 4 、(R b ) n And R is a A compound of formula (I) as defined above in the various embodiments.
In some embodiments, in the compounds of formula (I-5), formula (I-6), formula (I-7) or formula (I-8),
a represents CO or CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.gSuch as F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
(R a ) m Represents that the benzene ring is substituted by m R a Substituted, each R a The structural formulae are the following, which are identical or different and each independently of the others:
wherein,,
r represents chlorine, bromine, iodine, hydroxyl, a leaving group (e.g. -N 3 Chlorine, bromine, iodine, sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl-oxy (TfO-) or p-toluenesulfonyloxy (TsO-), NR 7 R 8 Or a group W 1 ，
Wherein R is 7 And R is 8 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 2-6 alkynyl-C 1-6 Alkylene- (e.g. C) 2-6 alkynyl-C 1-4 Alkylene-or C 2-6 alkynyl-C 1-3 Alkylene-, e.g. ethynyl-methylene-, ethynyl-ethylene-, ethynyl-propylene-, ethynyl-butylene-, ethynyl-pentylene-, or ethynyl-hexylene-), C 2-6 alkenyl-C 1-6 Alkylene- (e.g. C) 2-6 alkenyl-C 1-4 Alkylene-or C 2-6 alkenyl-C 1-3 Alkylene-, e.g. vinyl-methylene-, vinyl-ethylene-, vinyl-propylene-, vinyl-butylene-, vinyl-pentylene-, or vinyl-hexylene-), optionally substituted 4-to 15-membered (e.g. 4-11 membered, 4-to 10 membered,
4 to 9, 4 to 8, 4 to 7, 4 to 6, 5 to 15, or 5 to 9) nitrogen-containing heterocyclyl, or R 2a -R 1a -, wherein R is 1a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 2a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl, or leaving groups (e.g. -N) 3 Chlorine, bromine, iodine, sulfonate groups such as methanesulfonyloxy (MsO-), trifluoromethanesulfonyl oxy (TfO-), or p-toluenesulfonyloxy (TsO-); and
group W 1 The structure of the following formula is shown:
Wherein ring W 2 Represents an optionally substituted nitrogen-containing heterocyclic group (e.g., an optionally substituted 4-to 20-membered nitrogen-containing heterocyclic group), each ring W 3 Identical or different and each independently represents an optionally substituted nitrogen-containing heterocyclylene group (e.g. an optionally substituted 4-to 20-membered nitrogen-containing heterocyclylene group), t represents an integer 1 or 2, and ring W 4 Represents optionally substituted aryl (e.g. optionally substituted 6-to 10-membered aryl), optionally substituted heteroaryl (e.g. optionally substituted 5-to 10-membered heteroaryl) or optionally substituted heterocyclyl (e.g. 4-to 15-membered nitrogen containing heterocyclyl);
R 5 and R is 6 Identical or different and each independently represents hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group is optionally interrupted by one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R c And/or one or more (e.g., 1-20, or 1-15, 1-10, 1-9)1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R d Or one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d To break carbon-carbon bonds between one or more pairs (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2 pairs, or 1 pair) of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently optionally further substituted with a moiety selected from deuterium, (e.g., optionally deuterated C) 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluoro, chloro, bromo or iodo), cyano, optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-、Ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof;
or (b)
R and R 5 Together with the carbon atom to which they are attached form a carbonyl group, R 6 Represents hydrogen, optionally substituted methyl, or optionally substituted straight or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group is optionally interrupted by one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R c And/or one or more (e.g. 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R d Or one or more (e.g., 1-20, or 1-15, 1-10, 1-9, 1-8),
1-7、1-6、1-5、1-4、1-3 or 1-2, or 1) groups R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d One or more pairs of the main carbon chains (e.g., 1-15, 1-10, 1-9, 1-8, 1-7, 1-6,
1-5, 1-4, 1-3, or 1-2 pairs, or 1 pair) of adjacent carbon atoms; each group R c Selected from O,
N(R e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、
N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy,
CD 3 -O-, ethoxyA radical, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy group), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or
CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、
ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、
NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -sum of
NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
(R b ) n represents the benzene ring is substituted by n R b Substituted, each R b Identical or different and each independently represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxyPropoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), C 2-6 Alkenyl (e.g. ethenyl, propenyl or butenyl), or C 2-6 Alkynyl (e.g., ethynyl, propynyl, or butynyl); and
m represents an integer 1, 2, 3 or 4, n represents an integer 0, 1, 2 or 3, and the sum of m and n is an integer 1, 2, 3 or 4; wherein when R and R 5 Together with the carbon atom to which they are attached form a carbonyl group and R 6 When representing hydrogen, m represents an integer 1, 2 or 3, n represents an integer 1, 2 or 3, and the sum of m and n is an integer 2, 3 or 4;
With the proviso that the following compounds and compounds of formula (I') are excluded:
When A represents CH 2 Or C (O), and R represents unsubstituted piperazinyl, m represents an integer 1 and n represents an integer 0;
when A represents CH 2 Or C (O), and R a Represents H 2 N-CH 2 -when m represents an integer 1 and n represents an integer 0;
when a represents C (O), and R represents bromine, m represents an integer 1 and n represents an integer 0; and
a compound of formula (I'):
wherein A represents CH 2 Or C (O), and R represents unsubstituted piperaquineA pyridyl group or a methylamino-substituted piperidyl group.
In some embodiments, provided are specific compounds of formula (I) of table 1 below and salts (including pharmaceutically acceptable salts, e.g., their hydrochloride salts), prodrugs, solvates, isotopically enriched analogs, polymorphs, stereoisomers (including enantiomers and diastereomers), or mixtures of stereoisomers thereof:
table 1 compounds of the present disclosure
A compound of formula (II)
The present disclosure provides a compound of formula (II) or a salt (including pharmaceutically acceptable salts), stereoisomer (including enantiomers), solvate, isotopically enriched analog, prodrug, or polymorph thereof:
PBM-R f -LIN-ULM
formula (II)
Wherein PBM, R f LIN and ULM are as defined above for the compounds of formula (II).
The compounds of formula (II) of the present disclosure are not compounds of:
3- (4- ((3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) pyrrolidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) azetidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione; and
2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) azetidin-1-yl) methyl) isoindoline-1, 3-dione.
A compound of formula (II) of the present disclosure or a salt (including pharmaceutically acceptable salts), stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph thereof can bind to a target protein, recruit the target protein to E3 ubiquitin ligase for ubiquitination labeling and degradation. The compounds of formula (II) of the present disclosure are capable of specifically targeting a particular class or family of target proteins, exhibiting a broad range of pharmacological activity through degradation/inhibition of a variety of different classes or families of target proteins.
In some embodiments, specific target proteins include, but are not limited to, target proteins in table 2 below:
TABLE 2 specific target proteins applicable
In some embodiments, PBM-R f May be a small molecule ligand that binds to a specific target protein including, but not limited to, epidermal growth factor receptor (epidermal growth factor receptor, EGFR), cyclin-dependent kinase 4/6 (Cyclin-dependent kinase 4/6, CDK 4/6), anaplastic lymphoma kinase (anaplastic lymphoma kinase, ALK), activin receptor-like kinase 2 (ALK 2), fibroblast growth factor receptor (fibroblast growth factor receptors, FGFRs), proto-oncogene tyrosine protein kinase receptor RET (proto-oncogene tyrosine-protein kinase receptor RET), focal kinase (Focal adhesion kinase, FAK), breakpoint cluster region (breakpoint cluster region, BCR) -Abbe leukemia virus (Abelson leukemia virus, ABL) (BCR-ABL), bruton tyrosine kinase (Bruton tyrosine kinase, BTK), androgen receptor (Androgen receptor, AR), estrogen receptor (Estrogen receptor, ER), bromodomain and end ectodomain protein (Brom) odomain and extra-terminal domain protein, BET), interleukin-1receptor associated kinase 4 (Intereukin-1 receptor-associated kinase, IRAK4), cyclin-dependent kinase 9 (Cyclin-dependent kinase 9, CDK 9), histone lysine N-methyltransferase EZH2 (Histone-lysine N-methyltransferase EZH2, EZH 2), neurotrophic factor receptor tyrosine kinase (neurotrophic receptor tyrosine kinase, NTRK), src homology 2-domain containing protein tyrosine phosphatase (Src homolog 2domain containing protein tyrosine phosphatase,SHP2), poly (ADP-ribose) polymerase 1, PARP), signal transcripts and transcriptional activator protein 3 (signal transducers and activators of transcription, STAT 3), FMS-like tyrosine kinase 3 (FMS-like tyrosine kinase 3, FLT 3), BCL-2 (B cell lymphoma 2) family proteins, SOS Ras/Rac guanosine nucleotide exchange factor 1 or GTPase (KRAKRAS); KRAS).
In some embodiments, the PBM comprises a structure selected from the following formulas:
wherein the method comprises the steps of
(R 1 ) p1 The benzene ring in the formula (PBM-1) is substituted with p 1R 1 Substituted, each R 1 The same or different and each independently represents halogen, hydroxy, NH 2 、NO 2 Cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 2 ) p2 the quinazoline ring in the formula (PBM-1) is substituted with p 2R 2 Substituted, each R 2 Identical or different and each independently represents halogen, NO 2 Cyano, halo C 1-6 Alkyl, C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, halo C 1-10 Alkoxy, -O-optionally substituted heterocyclyl, or-NHC (O) R 3 Wherein R is 3 Is C 1-10 Alkyl, deuterated C 1-10 Alkyl or C 2-10 Alkenyl radicals, e.g. R 2 Represents methyl, methoxy,
For example->
p1 represents an integer 1, 2, 3, 4 or 5;
p2 represents an integer of 1, 2, or 3;
(R 4 ) p3 the benzene ring in the formula (PBM-2) is substituted with p 3R 4 Substituted, each R 4 Identical or different and each independently represents halogen, nitro, cyano, halo C 1-6 Alkyl, C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy or-NHC (O) R 15a Wherein R is 15a Is C 1-10 Alkyl, deuterated C 1-10 Alkyl or C 2-10 Alkenyl radicals, e.g. R 4 Represents methyl, methoxy, nitro or
p3 represents an integer 1, 2, 3 or 4;
(R 5 ) p4 the 1H-indole ring in the formula (PBM-2) is substituted with p 4R 5 Substituted, p4 represents an integer of 0, 1, 2 or 3, and each R 5 Identical or different and each independently represents hydrogen, C 1-10 Alkyl or deuterated C 1-10 An alkyl group;
R 6 represents hydrogen, C 1-10 Alkyl or deuterated C 1-10 An alkyl group;
(R 7 ) p5 the benzene ring in the formula (PBM-3) is substituted with p 5R 7 Substituted, each R 7 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, NO 2 、NH 2 Or cyano;
p5 represents an integer of 0, 1, 2, 3, 4 or 5;
R 8 represents substituted or unsubstituted C 3-15 Cycloalkyl groups such as cyclopentyl;
(R 9 ) p6 the benzene ring in the formula (PBM-4) is substituted with p 6R 9 Substituted, each R 9 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, NO 2 、NH 2 、C 1-6 Alkoxy, halo C 1-6 Alkoxy, or cyano;
p6 represents an integer of 2, 3, 4 or 5;
R 10 represent C 6-10 Aryl, or heteroaryl comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 The aryl and the heteroaryl are each optionally substituted with one or more R b1 Substitution, each R b1 The same or different and are each independently halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 11 ) p7 the benzene ring and the pyridine ring in the formula (PBM-5) are each optionally substituted with p 7R 11 Substituted, each p7 is the same or different and each independently represents an integer of 0, 1, 2 or 3, and each R in the formula (PBM-5) 11 Identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
R 12 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
r in formula (PBM-6) 13 Represents hydrogen, C 1-10 Alkyl (e.g
) Deuterated C 1-10 Alkyl or halo C 1-10 An alkyl group;
R 14 representation of
Wherein (R) b2 ) p8 Represents the piperidine ring optionally substituted by p 8R b2 Substituted, each R b2 Identical or different and each independently represents deuterium, halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, p8 represents an integer 1, 2, 3, 4 or 5;
ring A in formula (PBM-7) represents C 6-10 Aryl or 5-to 20-membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, said ring A optionally being substituted with one or more R b3 Substitution, each R b3 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 2-6 Alkenyl, or C 2-6 Alkynyl;
ring B in formula (PBM-7) represents C 3-15 Cycloalkyl or 3-to 20-membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, wherein the ring B is optionally substituted with one or more R b4 Substitution, each R b4 Identical or different and are each independently deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
ring C in formula (PBM-7) represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, said ring C optionally being substituted with one or more R b5 Substitution, each R b5 Identical or different andeach independently is deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
r in formula (PBM-8) 15 Represents a 4-to 20-membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more R b6 Substitution, each R b6 The same or different and are each independently halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 16 ) p9 the benzene ring in the formula (PBM-8) is substituted with p 9R 16 Substituted, each R 16 Identical or different and each independently represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 Alkyl, p9 represents an integer 1, 2, 3 or 4;
x of the formula (PBM-9) 1 Represents N or CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents N or CR 17 Wherein R is 17 Is hydrogen or represents a bond and X 3 Represents CH or N;
R 18 and R is 19 Each independently represents hydrogen or represents a bond;
(R 20 ) p10 the benzene ring in the formula (PBM-9) is substituted with p 10R 20 Substituted, each R 20 Identical or different and each independently represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, -C 1-3 alkylene-C (O) NH-heteroaryl or halogen, said aryl and heteroaryl each independently being optionally substituted with one or more R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p10 represents an integer of 1, 2, 3 or 4;
R 21 represents bond, deuterium, hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, or C 1-6 An alkoxy group;
R 22 represents hydrogen, halogen, cyano, or amino;
wherein R is 17 、R 18 、R 19 And R is 21 Not both hydrogen and R 17 、R 18 、R 19 And R is 21 Not simultaneously being a bond, R 17 、R 18 、R 19 And R is 21 Represents a key, wherein
When R is 18 When the bond is represented, R is the same as 18 The ring carbon atoms to which they are attached being directly attached R f ，X 2 Represents CH or N, and R 19 Is hydrogen and R 21 Not a bond;
when X is 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And
R 19 are all hydrogen and R 21 Not a bond;
when R is 19 When the bond is represented, R is the same as 19 The ring nitrogen atom being bound directly to R f ，X 2 Represents N or CH, and R 18 Is hydrogen and R 21 Not a bond; and
when R is 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And X is 2 Represents N or CH and R 18
And R is 19 Are all hydrogen;
(R 23 ) p11 the cyclopentene ring in the formula (PBM-10) is substituted with p 11R 23 Substituted, each R 23 Identical or different and each independently represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 Alkyl, p11 represents an integer of 2, 3, or 4;
(R 24 ) p12 the pyridine in the formula (PBM-10) is substituted with p 12R 24 Substituted, each R 24 Identical or different and each independently represents halogen, -C 1-3 alkylene-OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 Alkyl, p12 represents an integer of 1, 2, or 3;
R 25 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
x in formula (PBM-11) 4 Represents CR 26 Or a fragment
Wherein the symbol # denotes a symbol denoted by X 4 Adjacent N's connection points, the symbol # denotes X 5 And R is 26 Represents deuterium, hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, -C (O) -deuterated C 1-6 Alkyl or-C (O) NR b9 R b10 Wherein R is b9 、R b10 Identical or different and each independently represents hydrogen, C 1-6 Alkyl or deuterated C 1-6 An alkyl group;
x in formula (PBM-11) 5 Represents N or CR 27 Wherein R is 27 Represents hydrogen, deuterium, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
X 6 and X 7 Each independently represents CH or N;
R 28 represents a bond or an optionally substituted heteroarylene (e.g., a halogen substituted heteroarylene);
R 29 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, or optionally substituted C 3-7 Cycloalkyl;
R 30 and R is 31 Identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-12) 32 Represents hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
R 33 represents hydrogen, cyano, halogen,C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
(R 34 ) p13 the benzene ring in the formula (PBM-13) is substituted with p 13R 34 Substituted, each R 34 The radicals are identical or different and each independently represents halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
p13 represents an integer of 1, 2, 3, 4 or 5;
R 35 represents NR b11 R b12 Wherein R is b11 、R b12 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
(R 36 ) p14 the benzene ring in the formula (PBM-14) is optionally substituted with p 14R 36 Substituted, p14 represents an integer of 1, 2 or 3, each R in the formula (PBM-14) 36 The radicals are identical or different and each independently represents halogen, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
R 37 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
x in the formula (PBM-15) 8 、X 9 、X 10 、X 11 And X 12 Identical or different and each independently represents N or CH;
R 38 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl or deuterated C 1-6 Alkyl, R b14 Represents hydrogen or C 1-6 An alkyl group;
(R 40 ) p15 the said compound of formula (PBM-15) containing X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p15 represents an integer of 0, 1, 2, 3 or 4;
R 41 represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 42 ) p16 the benzene ring in the formula (PBM-16) is optionally substituted with p 16R 42 Substituted, each R in formula (PBM-16) 42 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
each p16 is the same or different and each independently represents an integer of 0, 1, 2, 3 or 4;
(R 43 ) p17 The benzene ring in the formula (PBM-17) is substituted with p 17R 43 Substituted, p17 represents an integer of 0, 1, 2, 3 or 4, each R in the formula (PBM-17) 43 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 44 ) p18 the benzene ring in the formula (PBM-18) is optionally substituted with p 18R 44 Substituted, each R 44 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p18 represents an integer of 0, 1, 2, 3 or 4;
(R 45 ) p19 the 4-oxo-3, 4-dihydroquinazoline ring in the formula (PBM-18) is substituted with p19 Rs 45 Substituted, each R 45 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p19 represents an integer 1, 2, 3 or 4;
(R 46 ) p20 the benzene ring in the formula (PBM-19) is substituted with p 20R 46 Substituted, each R 46 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p20 represents an integer of 1, 2, 3,4 or 5;
R 47 represents halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 48 ) p21 the quinoline ring in the formula (PBM-20) is substituted with p 21R 48 Substituted, each R 48 Identical or different and each independently represents halogen, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p21 represents an integer of 1, 2, 3 or 4;
(R 49 ) p22 the benzene ring in the formula (PBM-20) is substituted with p 22R 49 Substituted, each R 49 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p22 represents an integer 2, 3 or 4;
r in formula (PBM-21) 50 represents-NHC (O) -or-C (O) NH-;
R 51 represents-NH-or ethynylene;
(R 52 ) p23 the benzene rings in the formula (PBM-21) are each optionally substituted with p 23R 52 Substituted, each R 52 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
each p23 is the same or different and each independently represents an integer of 0, 1, 2, 3 or 4;
ring D in formula (PBM-21) represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, (R) 53 ) p24 Indicating that the ring D is optionally p24R 53 Substitution, each R 53 Identical or different and each independently represents an optionally substituted 5-to 15-membered heteroaryl, deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p24 represents an integer of 0, 1, 2, or 3;
r in formula (PBM-22) 54 、R 55 、R 56 And R is 57 Wherein R is the same or different and each independently represents hydrogen, halogen, or hydroxy 54 、R 55 、R 56 And R is 57 When one of them represents a bond, the benzene ring or methylene group in the formula (PBM-22) to which the bond is attached is directly attached to R f ；
The symbol of the double bond in the formula (PBM-22)
Represents a bond that may be in a steric configuration (cis or trans, or E-or Z-configuration);
x in the formula (PBM-23) 13 represents-O-or-CH 2 -；
(R 58 ) p25 The 1,2,3, 4-tetrahydronaphthalene ring in the formula (PBM-23) is substituted with p 25R 58 Substituted, each R 58 The same or different and each independently represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p25 represents an integer of 1,2,3 or 4;
R 59 and R is 60 Wherein only one of them represents a bond and the other represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, where R is 59 And R is 60 When one of them represents a bond, the ring carbon atom in the formula (PBM-23) to which the bond is attached is directly attached to R f ；
Ring E in formula (PBM-24) represents a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S;
R 62 represents optionally substituted 5-to 15-membered heteroaryl, optionally substituted 5-to 15-membered heterocyclyl, deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
R 61 represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 An alkyl group;
r in formula (PBM-25) 63 Represents optionally substituted 5-to 15-membered heterocyclyl, deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
R 64 represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Substituents of alkoxy groups or any combination thereof;
(R 65 ) p26 the isoquinoline ring in the formula (PBM-26) is substituted with p 26R 65 Substituted, each R 65 The same or different and each independently represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C (O) NH 2 Deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p26 represents an integer of 1, 2, 3 or 4;
R 66 the same or different and each independently represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
x in formula (PBM-27) 14 Represents N or CR b23 Wherein R is b23 Represents hydrogen or halogen, X 15 Represents N or CH;
R 67 represents a bond, -C (O) NH-, or-NHC (O) -;
R 68 represents halogen、C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 69 represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl or-C 1-3 alkylene-C 3-6 Cycloalkyl;
R 70 represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group; or (b)
R 69 And R is 70 Together with the corresponding nitrogen and carbon atoms to which they are each attached form an optionally substituted 5-to 7-membered nitrogen containing heterocyclic ring;
R 71 represents hydrogen or a bond, R 72 Represents hydrogen or a bond, wherein R 71 And R is 72 Not both hydrogen and R 71 And R is 72 Wherein when R represents a bond and the other represents hydrogen 71 When the bond is represented, R is the same as 71 The ring carbon atoms to which they are attached being directly attached R f And when R 72 When the bond is represented, R is the same as 72 The ring carbon atoms to which they are attached being directly attached R f ；
R in formula (PBM-28) 74 Represent C 1-3 Alkylene or halogenated C 1-3 An alkylene group;
R 73 represents optionally substituted C 3-6 Cycloalkyl, halo C 3-6 Cycloalkyl, or optionally substituted C 1-6 An alkyl group;
r in formula (PBM-29) 75 Represent C 1-3 Alkylene or halogenated C 1-3 An alkylene group;
R 76 represent C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, or optionally substituted C 3-6 Cycloalkyl;
r in formula (PBM-30) 77 Represent C 1-3 Alkylene or halogenated C 1-3 An alkylene group;
R 78 represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 79 and R is 80 Identical or different and each independentlyRepresents hydrogen, optionally substituted C 1-10 Alkyl or optionally substituted C 3-6 Cycloalkyl;
R 81 represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
x in the formula (PBM-31) 16 representing-S-or fragments
Wherein when X is 16 In the case of-S-, X is contained in the formula (PBM-31) 16 And heteroaryl of nitrogen atom is thiazolyl, and when X 16 Representing fragment->
When, in formula (PBM-31), X is contained 16 And heteroaryl of nitrogen atom is pyridinyl;
X 17 represents N or CH;
R 82 represents hydrogen or optionally substituted C 1-10 An alkyl group;
R 83 represents hydrogen, -C 1-3 Alkylene-optionally substituted 4-to 10-membered heterocyclyl or optionally substituted 4-to 10-membered heterocyclyl;
R 84 represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-32) 85 And R is 86 Identical or different and each independently represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 87 representation-S (O) 2 NH 2 or-C (O) NH 2 ；
R in formula (PBM-33) 88 Represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 89 represent C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group; or (b)
R 88 And R is 89 Together with the corresponding carbon and nitrogen atoms to which they are each attached form an optionally substituted 4-to 6-membered heteroaryl ring or an optionally substituted 4-to 6-membered heterocycle;
R 90 Represents optionally substituted C 3-6 Cycloalkyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl or optionally substituted 4-to 10-membered heterocyclyl;
(R 91 ) p27 the pyridin-2 (1H) -one ring in formula (PBM-33) is substituted with p 27R 91 Substituted, each R 91 Identical or different and each independently represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p27 represents an integer of 1, 2 or 3;
ring F in formula (PBM-33) represents an arylene group or a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S; (R) 92 ) p28 Represents the ring F optionally being substituted by p 28R 92 Substitution, each R 92 Identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p28 represents an integer of 0, 1, 2, 3 or 4;
(R 93 ) p29 the benzene ring in the formula (PBM-34) is substituted with p 29R 93 Substituted, each R 93 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p29 represents an integer of 1, 2, 3, 4 or 5;
R 94 represents hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 95 represents NR b15 R b16 Wherein R is b15 、R b16 Identical or different andeach independently represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl;
x in the formula (PBM-35) 18 、X 19 And X 20 Identical or different and each independently represents CH or N, wherein X 18 、X 19 And X 20 Not both N and X 18 、X 19 、X 20 And the six-membered ring of nitrogen atoms is optionally further substituted with 1 or 2 groups selected from halogen, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Substituents of alkyl groups or any combination thereof;
x in the formula (PBM-35) 21 And X 22 Identical or different and each independently represents C or N, wherein X 21 And X 22 Not both are N;
(R 96 ) p30 the benzene ring in the formula (PBM-35) is substituted with p 30R 96 Substituted, each R 96 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p30 represents an integer of 1, 2, 3, 4 or 5;
(R 97 ) p31 the tetrahydropyrrole ring in formula (PBM-35) is optionally substituted with p 31R 97 Substituted, each R 97 The same or different and each independently represents hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p31 represents an integer of 0, 1, 2, 3, 4, 5 or 6;
R 98 、R 99 、R 100 Identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
x in the formula (PBM-36) 23 Represents CH or N;
R 101 represents a bond or-S-;
R 102 represents a bond or an optionally substituted 4-to 15-membered nitrogen-containing heterocyclic group;
R 103 represents a bond, halogen, amino, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, or optionally substituted 4-to 15-membered nitrogen containing heterocyclyl;
wherein R is 102 And R is 103 Not both being bonds, and R 102 And R is 103 Wherein only one of R is a bond 102 When the bond is represented, R is the same as 102 The ring carbon atoms to which they are attached being directly attached R f And when R 103 When the bond is represented, R is the same as 103 The ring carbon atoms to which they are attached being directly attached R f ；
(R 104 ) p32 The six-membered ring in the formula (PBM-36) is optionally substituted with p 32R' s 104 Substituted, each R 104 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p32 represents an integer of 0, 1, 2, 3 or 4;
(R 105 ) p33 the benzene ring in the formula (PBM-37) is optionally substituted with p 33R 105 Substituted, each R 105 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p33 represents an integer of 1, 2, 3 or 4;
(R 106 ) p34 the phthalazinone ring in formula (PBM-37) is optionally substituted with p 34R 106 Substituted, each R 106 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p34 represents an integer of 0, 1, 2, 3 or 4;
(R 107 ) p35 the 2H-indazole ring in formula (PBM-38) is optionally substituted with p35 Rs 107 Substituted, each R 107 Identical or different and each is independentIn situ represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p35 represents an integer of 0, 1, 2 or 3;
(R 108 ) p36 the benzene ring in the formula (PBM-38) is optionally substituted with p 36R 108 Substituted, each R 108 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p36 represents an integer of 0, 1, 2 or 3;
(R 109 ) p37 the 2H-indazole ring in formula (PBM-39) is optionally substituted with p 37R 109 Substituted, each R 109 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p37 represents an integer of 0, 1, 2 or 3;
(R 110 ) p38 the benzene ring in the formula (PBM-39) is optionally substituted with p 38R 110 Substituted, each R 110 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p38 represents an integer of 0, 1, 2 or 3;
(R 111 ) p39 the benzene ring in the formula (PBM-40) is optionally substituted with p 39R 111 Substituted, each R 111 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p39 represents an integer of 0, 1, 2, 3 or 4;
R 112 、R 113 、R 114 identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-41) 115 Represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 116 、R 117 、R 118 identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 119 ) p40 the benzene ring in the formula (PBM-41) is optionally substituted with p 40R 119 Substituted, each R 119 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p40 represents an integer of 0, 1, 2, 3 or 4;
r in formula (PBM-42) 120 、R 121 Identical or different and each independently represents hydrogen, halogen, C 1-3 Alkyl or halo C 1-3 An alkyl group;
R 122 represents bond, hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 123 the structure of the following formula is shown:
Wherein R is 124 Represents a bond or hydrogen; (R) 125 ) p41 Represents the benzene ring optionally substituted by p 41R 125 Substituted, each R 125 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p41 represents an integer of 0, 1, 2, 3 or 4; or (b)
R 123 The structure of the following formula is shown:
wherein (R) 126 ) p42 Represents the benzene ring optionally substituted by p 42R 126 Substituted, each R 126 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p42 represents an integer of 0, 1, 2, 3, 4 or 5;
wherein R is 122 And R is 124 Not both being bonds, and R 122 And R is 124 Wherein when R represents a bond 122 When the bond is represented, R is the same as 122 The ring nitrogen atom being bound directly to R f And when R 124 When the bond is represented, R is the same as 124 The ring carbon atoms to which they are attached being directly attached R f ；
(R 127 ) p43 The benzene ring in the formula (PBM-43) is optionally substituted with p 43R 127 Substituted, each R 127 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p43 represents an integer of 0, 1, 2, 3 or 4;
r in formula (PBM-45) 131 Represent C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydrogen;
R 132 Represent C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-to 8-membered nitrogen containing heterocyclyl or NR b11 R b12 Wherein R is b11 、R b12 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or optionally substituted 4-to 8-membered heterocyclyl;
(R 133 ) p46 the benzene ring in the formula (PBM-45) is optionally substituted with p 46R 133 Substituted, each R 133 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl groupOr halogenated C 1-6 An alkyl group;
p46 represents an integer of 0, 1, 2, 3 or 4;
(R 134 ) p47 the benzene ring in the formula (PBM-46) is optionally substituted with p 47R 134 Substituted, each R 134 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p47 represents an integer of 0, 1, 2, 3 or 4;
(R 135 ) p48 the benzene ring in the formula (PBM-46) is optionally substituted with p 48R 135 Substituted, each R 135 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p48 represents an integer of 0, 1, 2, 3 or 4;
ring H in formula (PBM-48) represents C 6-10 Arylene or C 6-10 Heteroarylene (R) 137 ) p49 Represents the ring H optionally being substituted by p 49R' s 137 Substitution, each R 137 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p49 represents an integer of 0, 1, 2, 3 or 4;
R 136 represents an optionally substituted 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, optionally via a group selected from hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 Substituent substitution of alkyl;
x in formula (PBM-49) 24 、X 25 、X 26 Each independently represents CH or N;
R 138 represents-C (O) NHR b19 、-NHC(O)-R b19 、-S(O) 2 NHR b19 、-NHS(O) 2 R b19 、-S(O) 2 R b19 or-P (O) (R b19 ) 2 Wherein each R is b19 Identical or different and each independently represents C 1-6 Alkyl or deuterated C 1-6 An alkyl group;
R 139 and R is 140 Each independently represents halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 141 ) p50 represents the benzene ring optionally substituted by p 50R 141 Substitution, each R 141 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p50 represents an integer of 0, 1, 2, 3 or 4; and
in the formula (PBM-50) (R) 143 ) p51 Represents the benzene ring optionally substituted by p 51R 143 Substitution, each R 143 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p51 represents an integer of 0, 1, 2,3, 4 or 5;
R 142 representation H, C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 144 ) p52 the quinazoline ring in formula (PBM-50) is optionally substituted with p 52R 144 Substitution, each R 144 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group; and
p52 represents an integer of 1, 2, or 3;
r in formula (PBM-51) f2 Represents a bond, or R f2 represents-NH-R f3 -C(O) -x-ray in the sense that, wherein the symbols denote the values of R f1 And R is f3 Represents optionally substituted C 3-8 Cycloalkyl;
(R 145 ) p53 1H-pyrrolo [2,3-b ] in the formula (PBM-51)]The pyridine ring is optionally substituted by p 53R 145 Substitution, each R 145 Each independently is cyano, halogen, hydroxy, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p53 represents an integer 0, 1, 2,3, 4 or 5;
(R 146 ) p54 the pyridine ring in the formula (PBM-51) is optionally substituted with p 54R 146 Substitution, each R 146 Each independently is cyano, halogen, hydroxy, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy or NR b25 R b26 Wherein R is b25 、R b26 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl, and p54 represents an integer 0, 1, 2 or 3;
(R) in the formula (PBM-52) 147 ) p55 Represents the benzene ring optionally substituted by p 55R 147 Substitution, each R 147 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 Alkoxy, and p55 represents an integer 0, 1, 2, 3, 4 or 5;
R 148 represents NHC (O) or C (O) NH;
(R 149 ) p56 the 1H-pyrazole ring of formula (PBM-52) is optionally substituted with p 56R 149 Substitution, each R 149 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 Alkoxy, and p56 represents an integer of 0, 1 or 2; and
x in the formula (PBM-53) 27 Represents N or CH;
R 150 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
ring I represents C 6-10 Arylene or 5 to 15 membered heteroarylene, (R) 151 ) p57 Represents the ring I optionally substituted by p 57R 151 Substitution, each R 151 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p57 represents an integer of 0, 1, 2, 3 or 4;
(R 152 ) p58 the said compound of formula (PBM-53) contains X 27 Optionally p 58R' s 152 Substituted, each R 152 Represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p58 represents an integer of 0, 1 or 2;
(R 153 ) p59 the benzene ring in the formula (PBM-53) is optionally substituted with p 59R 153 Substituted, each R 153 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p15 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM-R f -a small molecule ligand representing EGFR.
In some embodiments, PBM represents the structure of formula (PBM-1-1A), formula (PBM-1-1B), formula (PBM-1-1C), or formula (PBM-1-1D):
wherein in the formula (PBM-1-1A), the formula (PBM-1-1B), the formula (PBM-1-1C) and the formula (PBM-1-1D),
(R 1 ) p1 each independently represents that the benzene ring is substituted by p 1R 1 Substituted, each R 1 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, NH 2 、NO 2 Cyano, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
(R 2 ) p2 Each independently represents that the quinazoline ring is surrounded by p 2R 2 Substituted, each R 2 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), NO 2 Cyano, halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-10 Alkyl (e.g. C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl radical), deuterated C 1-10 Alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-10 Alkoxy (e.g. C 1-8 Alkoxy, C 1-6 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-10 Alkoxy (e.g. halogenated C 1-4 Alkoxy, e.g. trifluoromethoxy), -O-optionally substituted heterocyclyl (wherein heterocyclyl is, e.g. a 4-to 20-membered mono-or bicyclic heterocyclyl containing one or more, e.g. 1-4 or 1, 2, 3 or 4, heteroatoms selected from nitrogen, oxygen and sulphur), or-NHC (O) R 3 Wherein R is 3 Is C 1-10 Alkyl (e.g. C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl radical), deuterated C 1-10 Alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or C 2-10 Alkenyl (e.g. C 2-6 Alkenyl or C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, butenyl or pentenyl), e.g. R 2 Represents methyl, methoxy,
For example->
p1 represents an integer 1, 2, 3, 4 or 5; and
p2 represents an integer of 1, 2, or 3.
In some embodiments, R 2 Represents an-O-optionally substituted heterocyclyl group which is a 4-to 20-membered (e.g., 4-to 15-membered, 4-to 12-membered, 4-to 10-membered, 4-to 7-membered, or 4-to 6-membered) monocyclic or bicyclic heterocyclyl group containing one or more (e.g., 1-4 or 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur, including, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazacycloheptyl (e.g., 1, 4-diazacycloheptan-1-yl), azacyclooctyl, diazacyclooctyl, azabicyclo [ 3.1.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R 2 The representation is:
fluorine, chlorine, bromine or iodine;
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl;
methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy;
-NHC(O)-C 2-10 alkenyl groups, e.g. -NHC (O) -vinyl(i.e
) -NHC (O) -propenyl or-NHC (O) -butenyl; or (b)
In some embodiments, PBM represents the structure of formula (PBM-1-1), formula (PBM-1-2), formula (PBM-1-3), formula (PBM-1-4), or formula (PBM-1-5) below:
in some embodiments, the PBM represents a structure of the following formula (PBM-2-1A), formula (PBM-2-1B), formula (PBM-2-1C), formula (PBM-2-1D), or formula (PBM-2-1E):
wherein in the formula (PBM-2-1A), the formula (PBM-2-1B), the formula (PBM-2-1C), the formula (PBM-2-1D) and the formula (PBM-2-1E),
(R 4 ) p3 each independently represents that the benzene ring is substituted by p 3R 4 Substituted, each R 4 Identical or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), nitro, cyano, halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-10 Alkyl (e.g. C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl radical), deuterated C 1-10 Alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-10 Alkoxy (e.g. C 1-8 Alkoxy, C 1-6 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or-NHC (O) R 19a Wherein R is 19a Is C 1-10 Alkyl (e.g. C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl radical), deuterated C 1-10 Alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or C 2-10 Alkenyl (e.g. C 2-6 Alkenyl or C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, butenyl or pentenyl), e.g. R 4 Represents methyl, methoxy, nitro or
p3 represents an integer 1, 2, 3 or 4;
(R 5 ) p4 each independently represents that the 1H-indole ring is surrounded by p 4R' s 5 Substituted, each R 5 Identical or different and each independently represents C 1-10 Alkyl (e.g. C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl radical), or deuterated C 1-10 Alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.); and
p4 represents an integer of 0, 1, 2 or 3.
In some embodiments, PBM represents the following formula (PBM-2-1) or the structure of formula (PBM-2-2):
in some embodiments, PBM represents the structure of formula (PBM-3-1A), formula (PBM-3-1B), or formula (PBM-3-1C):
wherein in the formula (PBM-3-1A), the formula (PBM-3-1B) and the formula (PBM-3-1C),
(R 7 ) p5 Each independently represents that the benzene ring is substituted by p 5R 7 Substituted, each R 7 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), NO 2 、NH 2 Or cyano;
p5 represents an integer of 0, 1, 2, 3, 4 or 5;
R 8 each independently represents substituted or unsubstituted C 3-15 Cycloalkyl (e.g. substituted or unsubstituted C 3-10 Cycloalkyl or C 3-6 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl). In some embodiments, the C 3-15 Cycloalkyl groups optionally being substituted with one or more (e.g. 1-3, 1, 2 or3) C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-3-1) below:
in some embodiments, PBM represents the structure of formula (PBM-4-1A), formula (PBM-4-1B), formula (PBM-4-1C), or formula (PBM-4-1D):
wherein in the formula (PBM-4-1A), the formula (PBM-4-1B), the formula (PBM-4-1C) and the formula (PBM-4-1D),
(R 9 ) p6 each independently represents that the benzene ring is substituted by p 6R 9 Substituted, each R 9 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, C 1-6 Alkyl (e.g. C 1-6 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuteratedC 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), NO 2 、NH 2 、C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-), or cyano group,
p6 represents an integer of 2, 3, 4 or 5; and
R 10 each independently represents C 6-10 Aryl, or heteroaryl comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 The aryl and the heteroaryl are each optionally substituted with one or more (e.g., 1-6, such as 1, 2, 3, 4, 5, or 6) R b1 Substitution, each R b1 The same or different and each independently is halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, R 10 Represent C 6-10 Aryl, such as, but not limited to, phenyl or naphthyl, each of which is optionally substituted with one or more (e.g., 1-6, such as 1, 2, 3, 4, 5 or 6) R as defined above b1 And (3) substitution.
In some embodiments, R 10 Represents a heteroaryl group comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S. In a sub-embodiment, R 10 Represents a 5-to 14-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b ]Thiazolyl or imidazo [1,2-b]Pyridazine. Heteroaryl is optionally substituted with one or more (e.g., 1-6, such as 1, 2, 3, 4, 5 or 6) R as defined above b1 And (3) substitution.
In some embodiments, PBM represents the structure of formula (PBM-4-1) or formula (PBM-4-2) below:
in some embodiments, PBM represents the structure of formula (PBM-5-1A), formula (PBM-5-1B), formula (PBM-5-1C), or formula (PBM-5-1D):
wherein in the formula (PBM-5-1A), the formula (PBM-5-1B), the formula (PBM-5-1C) and the formula (PBM-5-1D),
(R 11 ) p7 each independently represents that the benzene ring and pyridine ring are each optionally substituted with p 7R 11 Substituted, each p7 is the same or different and each independently represents an integer of 0, 1, 2 or 3, each R 11 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.); and
R 12 each independently represents hydrogen、C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, PBM represents the structure of the following formula (PBM-5-1):
in some embodiments, PBM represents the structure of the following formula (PBM-6):
wherein the method comprises the steps of
R 13 Represents hydrogen, C 1-10 Alkyl (e.g. C 1-8 Alkyl, C 1-6 Alkyl or C 1-4 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl
Butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), deuterated C 1-10 Alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-10 Alkyl (e.g. halogenated C) 1-8 Alkyl or halo C 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
R 14 representation of
Wherein (R) b2 ) p8 Represents the piperidine ring is substituted by p 8R b2 Substituted, each R b2 Identical or different and each independently represents deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-orCH 2 ClCH 2 -O-), deuterated C 1-6 Alkoxy (e.g. perdeuterated C 1-4 Alkoxy radicals, e.g. CD 3 -O-、CD 3 CD 2 -O-, or CD 3 CD 2 CD 2 -O-)、NO 2 、NH 2 Or cyano, p8 represents an integer of 1, 2, 3, 4 or 5.
In some embodiments, PBM represents the structure of formula (PBM-6-1) or formula (PBM-6-2) below:
in some embodiments, PBM represents the structure of formula (PBM-49):
wherein the method comprises the steps of
X 24 、X 25 、X 26 Each independently represents CH or N;
R 138 represents-C (O) NHR b19 、-NHC(O)-R b19 、-S(O) 2 NHR b19 、-NHS(O) 2 R b19 、-S(O) 2 R b19 or-P (O) (R b19 ) 2 Wherein each R is b19 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-4 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.);
R 139 and R is 140 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl radical), Halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy groups such as trifluoromethoxy);
(R 141 ) p50 represents the benzene ring optionally substituted by p 50R 141 Substitution, each R 141 Each independently is halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy groups, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butylAcyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy groups such as trifluoromethoxy); and
p50 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-49-1A), formula (PBM-49-1B), formula (PBM-49-1C), or formula (PBM-49-1D):
wherein in the formula (PBM-49-1A), the formula (PBM-49-1B), the formula (PBM-49-1C), the formula (PBM-49-1D) and the formula (PBM-49-1E),
X 24 、X 25 、X 26 each independently represents CH or N;
R 138 represents-C (O) NHR b19 、-NHC(O)-R b19 、-S(O) 2 NHR b19 、-NHS(O) 2 R b19 、-S(O) 2 R b19 or-P (O) (R b19 ) 2 Wherein each R is b19 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-4 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.);
R 139 and R is 140 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy groups such as trifluoromethoxy);
(R 141 ) p50 represents the benzene ring optionally substituted by p 50R 141 Substitution, each R 141 Each independently is halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy groups such as trifluoromethoxy); and
p50 represents an integer of 0, 1, 2, 3 or 4.
In some embodimentsIn the case of X 24 And X 25 Each independently represents CH or N. In some sub-embodiments, X 24 Represents CH, X 25 And represents N. In some sub-embodiments, X 24 Represents CH, X 25 Represents CH. In some sub-embodiments, X 24 Represents N, X 25 Represents CH. In some sub-embodiments, X 24 Represents N, X 25 And represents N.
In some embodiments, X 26 Represents CH or N. In some sub-embodiments, X 26 And represents N. In some sub-embodiments, X 26 Represents CH.
In some embodiments, R 138 represents-C (O) NHR b19 、-NHC(O)-R b19 、-S(O) 2 NHR b19 、-NHS(O) 2 R b19 、-S(O) 2 R b19 or-P (O) (R b19 ) 2 Wherein each R is b19 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-4 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.). In some sub-embodiments, R 138 represents-P (O) (R b19 ) 2 Wherein each R is b19 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-4 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-5 Alkyl, perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.). In some sub-embodiments, R 138 represents-P (O) (CH 3 ) 2 。
In some embodiments, p50 represents an integer of 0, 1, 2, 3, or 4. In some sub-embodiments, p50 represents an integer of 2.
In some embodiments, PBM represents the structure of formula (PBM-49-1), formula (PBM-49-2), formula (PBM-49-3), formula (PBM-49-4), or formula (PBM-49-5) below:
in some embodiments, PBM represents the structure of the following formula (PBM-55):
wherein,,
R 157 represent C 6-10 Aryl, or heteroaryl comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 The aryl and the heteroaryl are each optionally substituted with one or more (e.g., 1-6, such as 1, 2, 3, 4, 5, or 6) substituents selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
R 158 Represents a 5-to 15-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, wherein the 5-to 15-membered heteroaryl group is optionally substituted with one or more substituents selected from: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
(R 159 ) p61 the isoindolinone ring in formula (PBM-55) is substituted with p 61R 159 Substituted, each R 159 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p61 represents an integer 0, 1, 2 or 3.
In some embodiments, R 157 Represent C 6-10 Aryl, such as, but not limited to, phenyl or naphthyl, each optionally substituted with one or more (e.g., 1-6, such as 1, 2, 3, 4, 5, or 6) substituents selected from the group consisting of: halogen (example)Such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, R 157 Represents a heteroaryl group comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S. In a sub-embodiment, R 157 Represents a 5-to 15-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolylIsoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ] ]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazo [1,2-b]Pyridazine. Heteroaryl groups are optionally substituted with one or more (e.g., 1-6, such as 1,2, 3, 4, 5, or 6) substituents selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, R 158 Represents a 5-to 15-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S. In a sub-embodiment, R 158 Represents a 5-to 15-membered monocyclic or bicyclic aromatic ring group containing 1-4 (e.g., 1 to 3, or 1 to 2, or 1) heteroatoms independently selected from oxygen, nitrogen and sulfur. In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, 6, 7-dihydro-5H-pyrrolo [1,2-c]Imidazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b ]Thiazolyl or imidazo [1,2-b]Pyridazine. Heteroaryl groups are optionally substituted with one or more (e.g., 1-6, such as 1,2, 3, 4, 5, or 6) substituents selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, PBM represents the structure of formula (PBM-55-1) or formula (PBM-55-2) below:
in some embodiments, PBM-R f -a small molecule ligand representing AR.
In some embodiments, PBM represents the structure of the following formula (PBM-7-1A):
wherein the method comprises the steps of
Ring A in formula (PBM-7-1A) represents C 6-10 Aryl or a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, (R) b3 ) t3 Meaning that ring A is optionally substituted with t 3R b3 Substitution, each R b3 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups, e.g. methyl, ethyl,Propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)、C 2-6 Alkenyl (e.g. ethenyl, propenyl or butenyl), or C 2-6 Alkynyl (e.g., ethynyl, propynyl, or butynyl);
ring B in formula (PBM-7-1A) represents C 3-15 Cycloalkyl or 3-to 20-membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, (R) b4 ) t4 Meaning that ring B is optionally substituted with t 4R b4 Substitution, each R b4 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
Ring C in formula (PBM-7-1A) represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, (R) b5 ) t5 Meaning that ring C is optionally substituted with t 5R b5 Substitution, each R b5 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
t3 represents an integer 1, 2, 3, 4, 5 or 6;
t4 represents an integer 1, 2, 3, 4, 5 or 6; and
t5 represents an integer 1 or 2.
In some embodiments, PBM represents the structure of the following formula (PBM-7-1A-1):
wherein the method comprises the steps of
In the formula (PBM-7-1A-1) (R b3 ) t3 Represents the benzene ring optionally substituted by t 3R b3 Substituted, each R b3 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)、C 2-6 Alkenyl (e.g. ethenyl, propenyl or butenyl), or C 2-6 Alkynyl (e.g., ethynyl, propynyl, or butynyl);
ring B in formula (PBM-7-1A-1) represents C 3-15 Cycloalkyl or 3-to 20-membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, wherein (R b4 ) t4 Representing said ring B optionally being substituted with t 4R b4 Substitution, each R b4 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (example)Such as halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
Q 1 Represents N or CH; and
in the formula (PBM-7-1A-1) (R b5 ) t5 Represents a nitrogen-containing heteroaryl group optionally substituted by t 5R b5 Substituted, each R b5 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
t3 represents an integer 1, 2, 3, 4, 5 or 6;
t4 represents an integer 1, 2, 3, 4, 5 or 6; and
t5 represents an integer 1 or 2.
In some embodiments, PBM represents the structure of formula (PBM-7-1), formula (PBM-7-2), formula (PBM-7-3), or formula (PBM-7-4) below:
in some embodiments, the PBM represents the structure of formula (PBM-8-1A), formula (PBM-8-1B), formula (PBM-8-1C), formula (PBM-8-1D), or formula (PBM-8-1E):
wherein in the formula (PBM-8-1A), the formula (PBM-8-1B), the formula (PBM-8-1C), the formula (PBM-8-1D) and the formula (PBM-8-1E),
R 15 each independently represents a 4 to 20 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, wherein the heterocyclyl is optionally substituted with one or more R b6 Substitution, each R b6 The same or different and each independently is halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.),C 1-6 alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
(R 16 ) p9 each independently represents that the benzene ring is substituted by p 9R 16 Substituted, each R 16 Identical or different and each independently represents halogen, C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), p9 represents an integer 1, 2, 3 or 4;
in some embodiments, PBM represents the structure of formula (PBM-8-1), formula (PBM-8-2), formula (PBM-8-3), or formula (PBM-8-4):
in some embodiments, PBM-R f -a small molecule ligand representing BTK.
In some embodiments, PBM represents the structure of the following formula (PBM-9):
wherein the method comprises the steps of
X of the formula (PBM-9) 1 Represents N or CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents N or CR 17 Wherein R is 17 Is hydrogen or represents a bond and X 3 Represents CH or N;
R 18 and R is 19 Each independently represents hydrogen or represents a bond;
(R 20 ) p10 the benzene ring in the formula (PBM-9) is substituted with p 10R 20 Substituted, each R 20 Identical or different and each independently represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, -C 1-3 alkylene-C (O) NH-heteroaryl or halogen (e.g., fluorine, chlorine, bromine or iodine), each of said aryl and heteroaryl groups independently being optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R' s b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
p10 represents an integer of 1, 2, 3 or 4;
R 21 represents a bond, deuterium, hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy);
R 22 represents hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, or amino;
wherein R is 17 、R 18 、R 19 And R is 21 Not both hydrogen and R 17 、R 18 、R 19 And R is 21 Not at the same time beBond and R 17 、R 18 、R 19 And R is 21 Represents a key, wherein
When R is 18 When the bond is represented, R is the same as 18 The ring carbon atoms to which they are attached being directly attached R f ，X 2 Represents CH or N, and R 19 Is hydrogen and R 21 Not a bond;
when X is 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And
R 19 are all hydrogen and R 21 Not a bond;
when R is 19 When the bond is represented, R is the same as 19 The ring nitrogen atom being bound directly to R f ，X 2 Represents N or CH, and R 18 Is hydrogen and R 21 Not a bond; and
when R is 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And X is 2 Represents N or CH and R 18
And R is 19 Are all hydrogen.
In some embodiments, R in formula (PBM-9) 20 represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, wherein the aryl group may be optionally substituted C 6-10 Aryl groups, including but not limited to, for example, phenyl or naphthyl, heteroaryl groups may be optionally substituted 5-to 14-membered monocyclic or bicyclic aromatic ring groups containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a sub-embodiment, R 20 represents-O-phenyl or-O-naphthyl, the phenyl or naphthyl optionally being substituted by one or more (e.g. 1-5, such as 1, 2, 3, 4 or 5) R' s b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl,Butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, R 20 represents-O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, or imidazo [2,1-b]Thiazolyl.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents N or CH.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents N and X 3 Represents CH.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents N and X 3 And represents N.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents N and X 3 Represents CH.
In some embodiments, R 19 Represents a bond, R 18 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents N and X 3 And represents N.
In some embodiments, when R 18 When the bond is represented, R is the same as 18 The ring carbon atoms to which they are attached being directly attached R f ，X 2 Represents CH or N, and R 19 Is hydrogen and R 21 Not a key.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents N and X 3 And represents N.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents N and X 3 Represents CH.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents CH, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents N and X 3 Represents CH.
In some embodiments, R 18 Represents a bond, R 19 Is hydrogen, R 21 Not a bond, X 2 Represents N, X 1 Represents N and X 3 And represents N.
In some embodiments, when X 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen and R 21 Not a key.
In some embodiments, when X 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, R 21 Not a bond, X 1 Represents N and X 3 Represents CH.
In some embodiments, when X 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, R 21 Not a bond, X 1 Represents N and X 3 And represents N.
In some embodiments, when X 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, R 21 Not a bond, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, when X 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, R 21 Not a bond, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And X is 2 Represents N or CH toR is R 18 And R is 19 Are all hydrogen.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents N, X 1 Represents N and X 3 Represents CH.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents N, X 1 Represents N and X 3 And represents N.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents N, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents N, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents CH, X 1 Represents N and X 3 Represents CH.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents CH, X 1 Represents N and X 3 And represents N.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents CH, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, when R 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen, and X 2 Represents CH, X 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, PBM represents the structure of formula (PBM-9-1A):
wherein the method comprises the steps of
X of the formula (PBM-9-1A) 1 Represents N or CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents N or CH, and X 3 Represents CH or N;
(R 20 ) p10 the benzene ring in the formula (PBM-9-1A) is substituted with p 10R 20 Substituted, each R 20 Identical or different and each independently represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, said aryl and heteroaryl each independently being optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
R 21 Represents deuterium, hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,Sec-butyloxy or tert-butyloxy), e.g. R 21 Represents hydrogen or methyl; and
R 22 represents hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, or amino.
In some embodiments, R of formula (PBM-9-1A) 20 represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, wherein the aryl group may be optionally substituted C 6-10 Aryl groups, including but not limited to, for example, phenyl or naphthyl, heteroaryl groups may be optionally substituted 5-to 14-membered monocyclic or bicyclic aromatic ring groups containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a sub-embodiment, R 20 represents-O-phenyl or-O-naphthyl, the phenyl or naphthyl optionally being substituted by one or more (e.g. 1-5, such as 1, 2, 3, 4 or 5) R' s b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, R 20 represents-O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, or imidazo [2,1-b]Thiazolyl.
In some embodiments, X of formula (PBM-9-1A) 1 Represents N, X 2 Represents N and X 3 Represents CH.
In some embodiments, X of formula (PBM-9-1A) 1 Represents N, X 2 Represents N and X 3 And represents N.
In some embodiments, X of formula (PBM-9-1A) 1 Represents N, X 2 Represents CH and X 3 Represents CH.
In some embodiments, X of formula (PBM-9-1A) 1 Represents N, X 2 Represents CH and X 3 And represents N.
In some embodiments, X of formula (PBM-9-1A) 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents N and X 3 And represents N.
In some embodiments, X of formula (PBM-9-1A) 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents N and X 3 Represents CH.
In some embodiments, X of formula (PBM-9-1A) 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents CH and X 3 And represents N.
In some embodiments, X of formula (PBM-9-1A) 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents CH and X 3 Represents CH.
In some embodiments, PBM represents the structure of formula (PBM-9-1) below:
in some embodiments, PBM represents the structure of formula (PBM-9-1B):
wherein the method comprises the steps of
X of the formula (PBM-9-1B) 1 Represents N or CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH or N;
(R 20 ) p10 the benzene ring in the formula (PBM-9-1B) is substituted with p 10R 20 Substituted, each R 20 Identical or different and each independently represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, said aryl and heteroaryl each independently being optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl groupFor example F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
R 21 Represents deuterium, hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or C 1-6 Alkoxy group(e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), e.g. R 21 Represents hydrogen or methyl; and
R 22 represents hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, or amino.
In some embodiments, R of formula (PBM-9-1B) 20 represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, wherein the aryl group may be optionally substituted C 6-10 Aryl groups, including but not limited to, for example, phenyl or naphthyl, heteroaryl groups may be optionally substituted 5-to 14-membered monocyclic or bicyclic aromatic ring groups containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a sub-embodiment, R 20 represents-O-phenyl or-O-naphthyl, the phenyl or naphthyl optionally being substituted by one or more (e.g. 1-5, such as 1, 2, 3, 4 or 5) R' s b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy radicalA radical such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or a halogenated C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, R 20 represents-O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, or imidazo [2,1-b]Thiazolyl.
In some embodiments, X of formula (PBM-9-1B) 1 Represents N and X 3 Represents CH.
In some embodiments, X of formula (PBM-9-1B) 1 Represents N and X 3 And represents N.
In some embodiments, X of formula (PBM-9-1B) 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH.
In some embodiments, X of formula (PBM-9-1B) 1 Represents CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 And represents N.
In some embodiments, PBM represents the structure of formula (PBM-9-2) below:
in some embodiments, PBM represents the structure of formula (PBM-10-1A) or formula (PBM-10-1B) below:
wherein in the formula (PBM-10-1A) and the formula (PBM-10-1B),
(R 23 ) p11 each independently represents that the cyclopentene ring is covered by p 11R 23 Substituted, each R 23 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), p11 represents an integer 2, 3, or 4;
(R 24 ) p12 each independently represents that the pyridine is substituted with p 12R 24 Substituted, each R 24 Identical or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), -C 1-3 alkylene-OH (e.g. -CH 2 -OH、-CH 2 CH 2 -OH、-CH 2 CH 2 CH 2 -OH)、C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated)C 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), p12 represents an integer 1, 2, or 3; and
R 25 each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, PBM represents the structure of formula (PBM-10-1) or formula (PBM-10-2) below:
in some embodiments, PBM represents the structure of formula (PBM-46-1A), formula (PBM-46-1B), or formula (PBM-46-1C):
wherein in the formula (PBM-46-1A), the formula (PBM-46-1B) and the formula (PBM-46-1C),
(R 134 ) p47 each independently represents a benzene ring optionally substituted by p 47R 134 Substituted, each R 134 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p47 represents an integer of 0, 1, 2, 3 or 4;
(R) in the formula (PBM-46-1A), the formula (PBM-46-1B) and the formula (PBM-46-1C) 135 ) p48 Each independently represents a benzene ring optionally substituted by p 48R 135 Substituted, each R 135 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy orC 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p48 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-46-1) below:
in some embodiments, the PBM represents the structure of formula (PBM-45-1A), formula (PBM-45-1B), formula (PBM-45-1C), formula (PBM-45-1D), or formula (PBM-45-1E):
wherein the method comprises the steps of
R 131 Represent C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or R 131 Represents hydrogen;
R 132 represents an optionally substituted 4-to 8-membered nitrogen-containing heterocyclic group;
(R 133 ) p46 the benzene ring in the formula (PBM-45-1A), the formula (PBM-45-1B), the formula (PBM-45-1C), the formula (PBM-45-1D), or the formula (PBM-45-1E) is optionally substituted with p 46R 133 Substituted, each R 133 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p46 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, R 131 Represents ethyl. In some embodiments, R 131 Represents hydrogen. In some embodiments, R 132 Represents an optionally substituted 4-to 8-membered heterocyclic group. In some embodiments, an optionally substituted 4-to 8-membered heterocyclyl is, for example, optionally substituted 4-to 8-membered containing one or more, for example 1-4 or 1, 2, 3 or 4, heteroatoms selected from nitrogen, oxygen and sulfur (example4-7 membered, 4-6 membered, 5-7 membered, or 5-6 membered) monocyclic or bicyclic heterocyclyl including, but not limited to, the following optionally substituted groups: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ]]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1) ]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 8-membered heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, 3-methyl-2-oxoimidazolidin-1-yl, or any combination thereof. In some embodiments, R 132 Represents piperidinyl optionally substituted by 3-methyl-2-oxoimidazolidin-1-yl. In some embodiments, p46 represents an integer of 0. In some embodiments, p46 represents 1, and R 133 Represents methoxy.
In some embodiments, PBM represents the structure of formula (PBM-45-2), formula (PBM-45-3), or formula (PBM-45-4):
in some embodiments, PBM-R f -small representing CDK4/6A molecular ligand.
In some embodiments, PBM represents the structure of formula (PBM-11-1A), formula (PBM-11-1B), formula (PBM-11-1C), or formula (PBM-11-1D):
Wherein the method comprises the steps of
R in the formula (PBM-11-1A), the formula (PBM-11-1B), the formula (PBM-11-1C) and the formula (PBM-11-1D) 26 Each independently represents deuterium, hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc), -C (O) -C 1-6 Alkyl (e.g. -C (O) -C 1-5 Alkyl or-C (O) -C 1-3 Alkyl radicals, e.g. -C (O) -CH 3 、-C(O)-CH 2 CH 3 ) (C (O) -deuterated C 1-6 Alkyl (e.g. -C (O) -deuterated C 1-5 Alkyl or-C (O) -deuterated C 1-3 Alkyl radicals, e.g. -C (O) -CD 3 ) or-C (O) NR b9 R b10 Wherein R is b9 、R b10 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuteriumSubstitute C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), and R b9 、R b10 Are not hydrogen at the same time;
x in the formula (PBM-11-1A), the formula (PBM-11-1B), the formula (PBM-11-1C) and the formula (PBM-11-1D) 5 Each independently represents N or CR 27 Wherein R is 27 Represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
X in the formula (PBM-11-1A), the formula (PBM-11-1B), the formula (PBM-11-1C) and the formula (PBM-11-1D) 6 And X 7 Each independently represents CH or N;
ring G in formula (PBM-11-1B) and formula (PBM-11-1D) each independently represents a heteroarylene group (e.g., an optionally substituted 5-to 20-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur);
in the formula (PBM-11-1B) (R b19 ) t6 Representing ring G by t 6R b19 Substituted, each R b19 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
In the formula (PBM-11-1D) (R b20 ) t7 Representing ring G by t 7R b20 Substituted, each R b20 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)Deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
R in the formula (PBM-11-1A), the formula (PBM-11-1B), the formula (PBM-11-1C) and the formula (PBM-11-1D) 29 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or optionally substituted C 3-7 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or cycloheptyl, optionally selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 Substituent substitution of alkyl);
formula (PBM-11-1A), formula (PBM-11-1B), formula (PBM-11-1C) and formula (PBM-11-1D) R in (a) 30 And R is 31 The same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
t6 represents an integer of 0, 1, or 2; and
t7 represents an integer of 0, 1, or 2.
In some embodiments, ring G represents an optionally substituted heteroarylene, e.g., an optionally substituted 5-to 14-membered monocyclic or bicyclic heteroarylene containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of heteroarylenes include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazolyl, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinylene, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, pyrazolo [1,5-a ]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrroles]Thiazolylene and imidazo [2,1-b]Thiazole subunits. Heteroarylene is optionally substituted with one or more (e.g., 1-4, such as 1,2, 3, or 4) substituents selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, PBM represents the structure of formula (PBM-11-1), formula (PBM-11-2), or formula (PBM-11-3) below:
in some embodiments, PBM-R f -a small molecule ligand representing ALK.
In some embodiments, PBM represents the structure of formula (PBM-12-1A), formula (PBM-12-1B), formula (PBM-12-1C), or formula (PBM-12-1D):
wherein the method comprises the steps of
R in the formula (PBM-12-1A), the formula (PBM-12-1B), the formula (PBM-12-1C) and the formula (PBM-12-1D) 32 Each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.); and
r in the formula (PBM-12-1A), the formula (PBM-12-1B), the formula (PBM-12-1C) and the formula (PBM-12-1D) 33 Each independently represents hydrogen, cyano, halogen (e.g., fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, PBM represents the structure of formula (PBM-12-1) below:
in some embodiments, PBM represents the structure of the following formula (PBM-13):
wherein the method comprises the steps of
(R 34 ) p13 The benzene ring in the formula (PBM-13) is substituted with p 13R 34 Substituted, each R 34 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, amino, cyano, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.);
p13 represents an integer of 1, 2, 3, 4 or 5; or (b)
R 35 Represents NR b11 R b12 Wherein R is b11 、R b12 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, PBM represents the structure of formula (PBM-13-1) below:
in some embodiments, PBM represents the structure of formula (PBM-14), formula (PBM-14-1A), or formula (PBM-14-1B):
wherein the method comprises the steps of
(R 36 ) p14 The benzene ring in the formula (PBM-14) is optionally substituted with p 14R 36 Substituted, p14 represents an integer of 1, 2 or 3, each R 36 Identical or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), amino, cyano, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, e.gSuch as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.); and
R 37 represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, PBM represents the structure of formula (PBM-14-1) below:
In some embodiments, PBM represents the structure of the following formula (PBM-15):
wherein the method comprises the steps of
X in the formula (PBM-15) 8 、X 9 、X 10 、X 11 And X 12 Identical or different and each independently represents N or CH;
R 38 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), R b14 Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
(R 40 ) p15 the said compound of formula (PBM-15) containing X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated)C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p15 represents an integer of 0, 1, 2, 3 or 4; and
R 41 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R in formula (PBM-15) 38 Representing a key. In other words, the X-containing compound in the formula (PBM-15) 11 And X 12 Is directly linked to-NH-.
In some embodiments, R in formula (PBM-15) 38 Represents an optionally substituted methylene group (e.g., a halogen substituted methylene group).
In some embodiments, PBM represents the structure of formula (PBM-15-1A), formula (PBM-15-1B), or formula (PBM-15-1C):
wherein the method comprises the steps of
X 8 、X 9 And X 10 Identical or different and each independently represents N or CH;
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), R b14 Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
(R 40 ) p15 represents the content X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl radical), Deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p15 represents an integer of 0, 1, 2, 3 or 4; and
R 41 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, PBM represents the structure of formula (PBM-15-1D), formula (PBM-15-1E), or formula (PBM-15-1F):
wherein the method comprises the steps of
X 9 And X 10 Identical or different and each independently represents N or CH;
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), R b14 Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
(R 40 ) p15 represents the content X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p15 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-15-1) or formula (PBM-15-2) below:
in some embodiments, PBM-R f -a small molecule ligand representing FAK.
In some embodiments, PBM represents the structure of the following formula (PBM-15-1G):
wherein the method comprises the steps of
X in the formula (PBM-15-1G) 8 、X 11 And X 12 Identical or different and each independently represents N or CH;
R 38 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), R b14 Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
(R 40 ) p15 the said compound of formula (PBM-15) containing X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 Identical or different and each independently represents halogen, C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p15 represents an integer of 0, 1, 2, 3 or 4; and
R 41 represents halogen, C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl groupOr perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R in formula (PBM-15-1G) 38 Representing a key. In other words, the X-containing compound of formula (PBM-15-1G) 11 And X 12 Is directly linked to-NH-.
In some embodiments, R in formula (PBM-15-1G) 38 Represents an optionally substituted methylene group (e.g., a halogen substituted methylene group).
In some embodiments, PBM represents the structure of formula (PBM-15-1H) or formula (PBM-15-1I):
wherein the method comprises the steps of
X 8 、X 11 And X 12 Identical or different and each independently represents N or CH;
Each R is b21 The same or different and each independently represents hydrogen or halogen;
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), R b14 Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
(R 40 ) p15 the said compound of formula (PBM-15) containing X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 Identical or different and each independently represents halogen, C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p15 represents an integer of 0, 1, 2, 3 or 4; and
R 41 represents halogen, C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl radical) Deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, the PBM represents the structure of formula (PBM-15-6), formula (PBM-15-7), formula (PBM-15-8), formula (PBM-15-9), formula (PBM-15-10), or formula (PBM-15-11) below:
in some embodiments, PBM represents the structure of the following formula (PBM-53):
wherein X is 27 Represents N or CH;
R 150 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
ring I represents C 6-10 Aryl or 5-to 15-membered heteroaryl, (R) 151 ) p57 Represents the ring I optionally substituted by p 57R 151 Substitution, each R 151 Identical or different and each is independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p57 represents an integer 0, 1, 2, 3 or 4;
(R 152 ) p58 the said compound of formula (PBM-53) contains X 27 Optionally p 58R' s 152 Substituted, each R 152 Represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p58 represents an integer 0, 1 or 2;
(R 153 ) p59 the benzene ring in the formula (PBM-53) is optionally substituted with p 59R 153 Substituted, each R 153 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p15 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, X 27 And represents N.
In some embodiments, X 27 Represents CH.
In some embodiments, R 150 Representing a key.
In some embodiments, R 150 Represents an optionally substituted methylene group, for example a methylene group optionally substituted by halogen, such as fluorine, chlorine, bromine or iodine.
In some embodiments, ring I represents C 6-10 Aryl or 5 to 15 membered mono-or bicyclic heteroaryl. In some embodiments, ring I represents C 6-10 Aryl or a 5-to 15-membered (e.g., 5-to 12-membered, 5-to 10-membered, 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, or 6-membered) monocyclic or bicyclic heteroaryl containing 1-4 (e.g., 1-3, or 1-2) heteroatoms selected from N, O and S. Examples of aryl groups include, but are not limited to, phenyl, naphthyl. Examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ] ]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridyl, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrrolyl]Thiazolyl and imidazo [2,1-b]Thiazolyl.
In some embodiments, (R) in formula (PBM-53) 151 ) p57 Represents the ring I optionally substituted by p 57R 151 Substitution, each R 151 Identical or different and each is independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p57 represents an integer 0, 1,2, 3 or 4.
In some embodiments, ring I represents isoindolinyl, optionally further substituted with p 57R 151 Substitution, each R 151 Identical or different and each is independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p57 represents an integer 0, 1, 2, 3 or 4. In some embodiments, p57 represents an integer of 0, 1, 2, 3, or 4. In some embodiments, ring I represents isoindolinyl, optionally further substituted with halo (e.g., fluoro, chloro, bromo, or iodo), oxo, and C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl).
In some embodiments, (R) 152 ) p58 The said compound of formula (PBM-53) contains X 27 Optionally p 58R' s 152 Substituted, each R 152 Represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p58 represents an integer of 0, 1 or 2. In some embodiments, each R 152 Each independently represents halogen(e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p58 represents an integer of 0, 1 or 2.
In some embodiments, (R) 153 ) p59 The benzene ring in the formula (PBM-53) is optionally substituted with p 59R 153 Substituted, each R 153 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p15 represents an integer of 0, 1, 2, 3 or 4. In some embodiments, each R 153 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine) or C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, ethoxy, propoxy, isopropylOxy, butoxy, sec-butyloxy or tert-butyloxy), and p15 represents an integer 0, 1, 2, 3 or 4.
In some embodiments, the PBM represents the structure of formula (PBM-53-1A), formula (PBM-53-1B), formula (PBM-53-1C), formula (PBM-53-2A), formula (PBM-53-2B), or formula (PBM-53-2C) below:
wherein X is 27 、R 150 、(R 151 ) p57 、(R 152 ) p58 And (R) 153 ) p59 As defined in the various embodiments of formula (PBM-53) and in the various sub-embodiments thereof.
In some embodiments, PBM represents the structure of formula (PBM-53-1), formula (PBM-53-2), formula (PBM-53-3), or formula (PBM-53-4):
in some embodiments, PBM-R f -a small molecule ligand representing RET.
In some embodiments, PBM represents the structure of formula (PBM-15-1J), formula (PBM-15-1K), or formula (PBM-15-1L):
wherein the method comprises the steps of
X 9 And X 10 Identical or different and each independently represents N or CH;
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), R b14 Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl);
(R 40 ) p15 represents the content X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p15 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-15-3), formula (PBM-15-4), or formula (PBM-15-5):
in some embodiments, the PBM represents the structure of formula (PBM-16-1A), formula (PBM-16-1B), formula (PBM-16-1C), formula (PBM-16-1D), or formula (PBM-16-1E):
wherein the method comprises the steps of
Formula (PBM-16-1A), formula (PBM-16-1B), formula (PBM-16-1C), formula (PBM-16-1D) and formula (PBM-16-1E) (R) 42 ) p16 Each independently represents that the benzene ring is optionally substituted with p 16R 42 Substituted, each R 42 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
each p16 is the same or different and each independently represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-16-1) below:
in some embodiments, PBM-R f -a small molecule ligand representing BET.
In some embodiments, PBM represents the structure of the following formula (PBM-17):
wherein the method comprises the steps of
(R 43 ) p17 The benzene ring in the formula (PBM-17) is substituted with p 17R 43 Substituted, each R 43 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p17 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-17-1) below:
in some embodiments, the PBM represents the structure of formula (PBM-18-1A), formula (PBM-18-1B), formula (PBM-18-1C), formula (PBM-18-1D), or formula (PBM-18-1E):
wherein the method comprises the steps of
Formula (PBM-18-1A), formula (PBM-18-1B), formula (PBM-18-1C), formula (PBM-18-1D) and formula (PBM-18-1E) 44 ) p18 Each independently represents that the benzene ring is substituted by p 18R 44 Substituted, each R 44 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p18 represents an integer of 0, 1, 2, 3 or 4;
formula (PBM-18-1A), formula (PBM-18-1B), formula (PBM-18-1C), formula (PBM-18-1D) and formula (PB)M-18-1E) (R) 45 ) p19 Each independently represents that the 4-oxo-3, 4-dihydroquinazoline ring is substituted with p 19R 45 Substituted, each R 45 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p19 represents an integer of 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-18-1) below:
in some embodiments, PBM-R f -a small molecule ligand representing BCR-ABL.
In some embodiments, PBM represents the structure of formula (PBM-19-1A) or formula (PBM-19-1B) below:
wherein the method comprises the steps of
Formula (PBM-19-1A) or formula (PBM-19-1B)) (R) 46 ) p20 Each independently represents that the benzene ring is substituted by p 20R 46 Substituted, each R 46 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p20 represents an integer of 1, 2, 3, 4 or 5; and
R 47 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, PBM represents the structure of formula (PBM-19-1) below:
in some embodiments, PBM represents the structure of formula (PBM-20-1A), formula (PBM-20-1B), formula (PBM-20-1C), or formula (PBM-20-1D):
wherein the method comprises the steps of
Formula (PBM-20-1A), formula (PBM-20-1B), formula (PBM-20-1C) and formula (PBM-20-1D) 48 ) p21 Each independently represents that the quinoline ring is substituted by p 21R 48 Substituted, each R 48 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p21 represents an integer of 1, 2, 3 or 4;
(P)BM-20-1A), formula (PBM-20-1B), formula (PBM-20-1C) and formula (PBM-20-1D) 49 ) p22 Each independently represents that the benzene ring is substituted by p 22R 49 Substituted, each R 49 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p22 represents an integer of 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-20-1) below:
in some embodiments, the PBM represents the structure of formula (PBM-21):
wherein the method comprises the steps of
R 50 represents-NHC (O) -or-C (O) NH-;
R 51 represents-NH-or ethynylene;
(R 52 ) p23 the benzene rings in the formula (PBM-21) are each optionally substituted with p 23R 52 Substituted, each R 52 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
Each p23 is the same or different and each independently represents an integer of 0, 1, 2, 3 or 4;
ring D in formula (PBM-21) represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, (R) 53 ) p24 Represents the ring D optionally being substituted by p 24R 53 Substitution, each R 53 Identical or different and each independently represents optionally substituted 5-to 15-membered heteroaryl, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
p24 represents an integer of 0, 1, 2, or 3.
In some embodiments, ring D in formula (PBM-21) represents a heteroaryl group comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S. In a sub-embodiment, ring D represents a 5-to 14-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridyl, pyrazolo [1,5-a]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazo [1,2-b]And a pyridazinyl group. Heteroaryl is optionally substituted with one or more (e.g., 1-6, such as 1,2,3, 4, 5, or 6) substituents, wherein the substituents are optionally selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof.
In some embodiments, R in formula (PBM-21) 53 Represents an optionally substituted 5-to 15-membered heteroaryl. In some embodiments, a 5-to 15-membered heteroaryl is a 5-to 14-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some sub-embodiments, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzeneBenzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ] ]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazo [1,2-b]And a pyridazinyl group. Heteroaryl is optionally substituted with one or more (e.g., 1-6, such as 1,2, 3, 4, 5, or 6) substituents, wherein the substituents are optionally selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof.
In some embodiments, R in formula (PBM-21) 51 represents-NH-.
In some embodiments, R in formula (PBM-21) 51 Represents an ethynylene group.
In some embodiments, the PBM represents the structure of formula (PBM-21-1A), formula (PBM-21-1B), formula (PBM-21-1C), formula (PBM-21-1D), or formula (PBM-21-1E):
Wherein the method comprises the steps of
Formula (PBM-21-1A), formula (PBM-21-1B), formula (PBM-21-1C), formula (PBM-21-1D) and formula (PBM-21-1E) 52 ) p23 Each independently represents that the benzene rings are each independently optionally substituted with p 23R 52 Substituted, each R 52 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p23 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-21-1) below:
in some embodiments, PBM represents the following formula (PBM-21-1F), formula (PBM-21-1G), formula (PBM-21-1H), formula (PBM-21-1I), or formula (PBM-21-1J):
wherein the method comprises the steps of
Each of the formula (PBM-21-1F), the formula (PBM-21-1G), the formula (PBM-21-1H), the formula (PBM-21-1I) and the formula (PBM-21-1J) (R) 52 ) p23 Each independently represents that the benzene rings are each independently optionally substituted with p 23R 52 Substituted, each R 52 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p23 represents an integer of 0, 1, 2, 3 or 4;
each ring D in formula (PBM-21-1F), formula (PBM-21-1G), formula (PBM-21-1H), formula (PBM-21-1I) and formula (PBM-21-1J) independently represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, (R) 53 ) p24 Represents the ring D optionally being substituted by p 24R 53 Substitution, each R 53 Identical or different and each independently represents an optionally substituted 5-to 15-membered heteroaryl, deuterium, halogen (e.g. fluorine, chlorine, bromine)Or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
p24 represents an integer of 0, 1, 2, or 3.
In some embodiments, each ring D in formula (PBM-21-1F), formula (PBM-21-1G), formula (PBM-21-1H), formula (PBM-21-1I), and formula (PBM-21-1J) independently represents a heteroaryl group comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S. In a sub-embodiment, ring D represents a 5-to 14-membered monocyclic or bicyclic aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl Oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazo [1,2-b]Pyridazine. Heteroaryl is optionally substituted with one or more (e.g., 1-6, such as 1,2,3, 4, 5, or 6) substituents, wherein the substituents are optionally selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-21-2):
in some embodiments, PBM represents the structure of the following formula (PBM-52):
wherein the method comprises the steps of
(R) in the formula (PBM-52) 147 ) p55 Represents the benzene ring optionally substituted by p 55R 147 Substitution, each R 147 Each independently is halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、F 2 ClC-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p55 represents an integer 0,1. 2, 3, 4 or 5;
R 148 represents NHC (O) or C (O) NH; and
(R 149 ) p56 the 1H-pyrazole ring of formula (PBM-52) is optionally substituted with p 56R 149 Substitution, each R 149 Each independently is halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、F 2 ClC-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p56 represents an integer 0, 1 or 2.
In some embodiments, (R) in formula (PBM-52) 147 ) p55 Represents that the benzene ring is substituted by p 55R 147 Substitution, wherein p55 represents an integer of 1, and R 147 Halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、F 2 ClC-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In some embodiments, R 147 Is F 2 ClC-O-。
In some embodiments, R 148 Represents NHC (O). In some embodiments, R 148 Represents C (O) NH.
In some embodiments, p56 represents an integer of 0.
In some embodiments, PBM represents the structure of formula (PBM-52-1A) or formula (PBM-52-1B) below:
wherein, (R) 147 ) p55 、R 148 And (R) 149 ) p56 Embodiments of formula (PBM-52)And the sub-embodiments thereof.
In some embodiments, PBM represents the structure of formula (PBM-52-1) below:
in some embodiments, PBM-R f -a small molecule ligand representing ER.
In some embodiments, PBM represents the structure of formula (PBM-22-1A), formula (PBM-22-1B), formula (PBM-22-1C), or formula (PBM-22-1D):
Wherein the method comprises the steps of
R 54 、R 55 、R 56 And R is 57 The same or different and each independently represents hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), or hydroxy; and
symbols of the double bond in the formulae (PBM-22-1A), (PBM-22-1B), (PBM-22-1C) and (PBM-22-1D)
Represents a bond that may be in a steric configuration (cis or trans, or E-or Z-configuration).
In some embodiments, the PBM represents the structure of formula (PBM-22-1), formula (PBM-22-2), formula (PBM-22-3), formula (PBM-22-4), formula (PBM-22-5), formula (PBM-22-6), formula (PBM-22-7), formula (PBM-22-8), formula (PBM-22-9), or formula (PBM-22-10) below.
In some embodiments, PBM represents the structure of formula (PBM-23-1A) or formula (PBM-23-1B) below:
wherein the method comprises the steps of
Each X in the formula (PBM-23-1A) and the formula (PBM-23-1B) 13 Each independently represents-O-or-CH 2 -；
Each of the formula (PBM-23-1A) and the formula (PBM-23-1B) (R) 58 ) p25 Each independently represents that the 1,2,3, 4-tetrahydronaphthalene ring is substituted with p 25R 58 Substituted, each R 58 The same or different and each independently represents hydrogen, hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p25 represents an integer of 1, 2, 3 or 4; and
R 59 and R is 60 Each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, the PBM represents the following formula (PBM-23-1), formula (PBM-23-2), formula (PBM-23-3), formula (PBM-23-4), formula (PBM-23-5), formula (PBM-23-6), formula (PBM-23-7), or formula (PBM-23-8):
in some embodiments, PBM-R f -a small molecule ligand representing IRAK 4.
In some embodiments, PBM represents the structure of the following formula (PBM-24):
wherein the method comprises the steps of
Ring E in formula (PBM-24) represents a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S;
R 62 represents an optionally substituted 5-to 15-membered heteroaryl, an optionally substituted 5-to 15-membered heterocyclyl, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.gSuch as CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
R 61 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, ring E in formula (PBM-24) represents a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S. In some embodiments, heteroarylene is a 5-to 14-membered monocyclic or bicyclic divalent aromatic ring group containing 1-4 (e.g., 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some sub-embodiments, examples of heteroarylene include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, and Isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2,1,3 ]]Oxadiazole subunits and benzo [2,1,3 ]]Thiadiazole subunit, benzo [1,2,3]Thiadiazole subunits, quinolinylene, isoquinolylene, naphthyridine subunits, cinnolinyl, quinazolinylene, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, pyrrolo [2,1-b]Thiazolylene, imidazo [2,1-b]Thiazolylene or imidazo [1,2-b]Pyridazine subunits. The heteroarylene group is optionally further substituted with one or more (e.g., 1-3, such as 1,2, or 3) substituents, wherein the substituents are optionally selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof.
In some embodiments, R in formula (PBM-24) 62 Represents an optionally substituted 5-to 15-membered heteroaryl. In some embodiments, a 5-to 15-membered heteroaryl is a 5-to 15-membered monocyclic or bicyclic aromatic ring group containing 1-4 (e.g., 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some sub-embodiments, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazo [1,2-b]And a pyridazinyl group. R is R 62 The heteroaryl group represented is optionally further substituted with one or more (e.g., 1-3, such as 1,2, or 3) substituents, wherein the substituents are optionally selected from the group consisting of: -N (R) b22 )-C 1-6 Alkylene-optionally substituted C 3-8 Cycloalkyl, -N (R) b22 ) -optionally halogenated C 1-6 Alkyl, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof, wherein each R b22 Independently represent hydrogen or C 1-3 An alkyl group. In some embodiments, R 62 The substituent of the heteroaryl group represented is-N (R b22 )-C 1-6 Alkylene-optionally substituted C 3-8 Cycloalkyl, wherein R is b22 Represents hydrogen or C 1-3 Alkyl (e.g., methyl). In some embodiments, C 1-6 Examples of alkylene groups include, but are not limited to, C 1-3 An alkylene group. In some embodiments, C 3-8 Examples of cycloalkyl groups include, but are not limited to, C 3-6 Cycloalkyl groups. In some embodiments, C 3-8 Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. C (C) 3-8 Cycloalkyl groups optionally are further substituted with one or more (e.g., 1-3, such as 1, 2, or 3) groups selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 Substituents that are alkyl-C (O) NH-, cyano-, or any combination thereof. In some embodiments, R 62 The substituent of the heteroaryl group represented is-N (R b22 ) -optionally halogenated C 1-6 Alkyl, wherein R is b22 Represents hydrogen or C 1-3 Alkyl (e.g., methyl). In some embodiments, optionally halogenated C 1-6 Examples of alkyl groups include, but are not limited to, optionally halogenated C 1-4 Alkyl, optionally halogenated C 1-3 Alkyl and optionally halogenated C 1-2 An alkyl group. In some embodimentsIn the scheme, optionally halogenated C 1-6 Representative examples of alkyl groups include, but are not limited to, -CH 2 -CF 3 。
In some embodiments, R in formula (PBM-24) 62 Represents an optionally substituted 5-to 15-membered heterocyclic group. In some sub-embodiments, "5-to 15-membered heterocyclyl" refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen, a single, double, or triple ring. In some sub-embodiments, examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azacyclooctyl, diazepanyl (e.g., 1, 4-diazepan-1-yl), and diazepanyl. The heterocyclic group is optionally substituted with one or more (e.g. 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-24-1) or formula (PBM-24-2) below:
in some embodiments, PBM represents the structure of the following formula (PBM-25):
wherein the method comprises the steps of
R in formula (PBM-25) 63 Represents an optionally substituted 5-to 15-membered heterocyclic group, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
R 64 represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted with one or more (e.g. 1 to 6, such as 1, 2, 3, 4, 5 or 6) groups selected from deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, e.g. methyl, ethyl, propylIsopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) or any combination thereof.
In some embodiments, R in formula (PBM-25) 63 Represents an optionally substituted 5-to 15-membered heterocyclic group. In some sub-embodiments, "5-to 15-membered heterocyclyl" refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen, a single, double, or triple ring. In some sub-embodiments, examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azacyclooctyl, diazacyclo-alkyl Heptyl (e.g., 1, 4-diazepan-1-yl) and diazepan. The heterocyclic group is optionally substituted with one or more (e.g. 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R in formula (PBM-25) 64 Represents an optionally substituted 5-to 20-membered (e.g. 5-to 15-membered, 5-to 10-membered or 5-to 6-membered) mono-or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S. In some sub-embodiments, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazo [1,2-b]And a pyridazinyl group. Heteroaryl is optionally further substituted with one or more (e.g., 1-3, such as 1,2, or 3) substituents, wherein the substituents are optionally selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, e.g. methyl, ethylPropyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-25-1), formula (PBM-25-2), or formula (PBM-25-3) below:
in some embodiments, PBM represents the structure of formula (PBM-26-1A) or formula (PBM-26-1B) below:
wherein the method comprises the steps of
Each of the formula (PBM-26-1A) and the formula (PBM-26-1B) (R) 65 ) p26 Each independently represents an isoquinoline ring surrounded by p 26R 65 Substituted, each R 65 The same or different and each independently represents hydrogen, hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxyEthoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), -C (O) NH 2 Deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p26 represents an integer of 1, 2, 3 or 4; and
R 66 the same or different and each independently represents hydrogen, hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, PBM represents the structure of formula (PBM-26-1) below:
in some embodiments, PBM represents the structure of the following formula (PBM-27):
wherein the method comprises the steps of
X in formula (PBM-27) 14 Represents N or CR b23 Wherein R is b23 Represents hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine), X 15 Represents N or CH;
R 67 represents a bond, -C (O) NH-, or-NHC (O) -;
R 68 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 69 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., halogenSubstitute C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) or-C 1-3 alkylene-C 3-6 Cycloalkyl (e.g., -methylene-cyclopropyl);
R 70 represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; or (b)
R 69 And R is 70 Together with the corresponding nitrogen and carbon atoms to which they are each attached form an optionally substituted 5-to 7-membered nitrogen containing heterocyclic ring; and
R 71 represents hydrogen or a bond, R 72 Represents hydrogen or a bond, wherein R 71 And R is 72 Not both hydrogen and R 71 And R is 72 Wherein when R represents a bond and the other represents hydrogen 71 When the bond is represented, R is the same as 71 The ring carbon atoms to which they are attached being directly attached R f And when R 72 When the bond is represented, R is the same as 72 The ring carbon atoms to which they are attached being directly attached R f 。
In some embodiments, R in formula (PBM-27) 67 Representing a key.
In some embodiments, in formula (PBM-27)R of (2) 67 represents-C (O) NH-or-NHC (O) -.
In some embodiments, R in formula (PBM-27) 69 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) or-C 1-3 alkylene-C 3-6 Cycloalkyl; and
R 70 represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R in formula (PBM-27) 69 And R is 70 Together with the corresponding nitrogen and carbon atoms to which they are each attached form an optionally substituted 5-to 7-membered nitrogen containing heterocyclic ring. In some embodimentsIn this scheme, 5-to 7-membered nitrogen-containing heterocycles include, but are not limited to, for example, 5-to 7-membered (e.g., 5-to 6-membered, 5-membered) heterocycles containing one nitrogen atom and optionally containing heteroatoms selected from nitrogen, oxygen and sulfur. The 5-to 7-membered nitrogen-containing heterocyclic ring is condensed with the pyrazole ring in the formula (PBM-27) to form a condensed ring. The 5-to 7-membered nitrogen-containing heterocycle is optionally substituted with one or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, 1 to 3, or 2) substituents selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, amino, cyano, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.).
In some embodiments, R is 69 And R is 70 The 5-to 7-membered nitrogen-containing heterocyclic ring formed together with the corresponding nitrogen and carbon atoms to which they are each attached is fused with an adjacent pyrazole ring to form the following group:
in some embodiments, PBM represents the structure of formula (PBM-27-1A):
wherein the method comprises the steps of
X 14 Represents N or CR b23 Wherein R is b23 Represents hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine), X 15 Represents N or CH;
R 67 represents-C (O) NH-or-NHC (O) -;
R 68 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 69 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) or-C 1-3 alkylene-C 3-6 Cycloalkyl (e.g., -methylene-cyclopropyl);
R 70 represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; or (b)
R 69 And R is 70 Together with the corresponding nitrogen and carbon atoms to which they are each attached form an optionally substituted 5-to 7-membered nitrogen containing heterocyclic ring.
In some embodiments, PBM represents the structure of formula (PBM-27-1B):
wherein the method comprises the steps of
X 14 Represents N or CR b23 Wherein R is b23 Represents hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine), X 15 Represents N or CH;
R 68 represents halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 69 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) or-C 1-3 alkylene-C 3-6 Cycloalkyl (e.g., -methylene-cyclopropyl);
R 70 represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; or (b)
R 69 And R is 70 Together with the corresponding nitrogen and carbon atoms to which they are each attached form an optionally substituted 5-to 7-membered nitrogen containing heterocyclic ring.
In some embodiments, R in formula (PBM-27-1A) and formula (PBM-27-1B) 69 Each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) or-C 1-3 alkylene-C 3-6 Cycloalkyl (e.g., -methylene-cyclopropyl).
In some embodiments, R in formula (PBM-27-1A) and formula (PBM-27-1B) 70 Each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R in formula (PBM-27-1A) 69 And R is 70 Each independently represents hydrogen.
In some embodiments, R in formula (PBM-27-1B) 69 Represents-methylene-cyclopropyl, R 70 Represents methyl.
In some embodiments of formula (PBM-27-1A) and formula (PBM-27-1B), R 69 And R is 70 The nitrogen-containing heterocyclic ring formed together with the corresponding nitrogen and carbon atoms to which they are each attached is fused with an adjacent pyrazole ring to form the following group:
in some embodiments, PBM represents the structure of formula (PBM-27-1), formula (PBM-27-2), or formula (PBM-27-3) below:
in some embodiments, the PBM represents the structure of formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D), or formula (PBM-28-1E):
wherein the method comprises the steps of
Each R in the formula (PBM-28-1A), the formula (PBM-28-1B), the formula (PBM-28-1C), the formula (PBM-28-1D) and the formula (PBM-28-1D) 74 Each independently represents a bond, C 1-3 Alkylene (e.g. methylene, ethylene or propylene) or halogenated C 1-3 Alkylene (e.g., halomethylene, haloethylene, or halopropylene); and
R 73 represents optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), halo C 3-6 Cycloalkyl (e.g. halogenated cyclopropyl, halogenatedCyclobutyl, halocyclopentyl or halocyclohexyl), or optionally substituted C 1-6 Alkyl (e.g. optionally substituted C 1-5 Alkyl, optionally substituted C 1-4 Alkyl or optionally substituted C 1-3 Alkyl groups, such as the following optionally substituted groups: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl). Optionally substituted C 1-6 Substituents for alkyl groups include, but are not limited to, for example, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally substituted C 6-10 Aryl (e.g., optionally substituted phenyl or optionally substituted naphthyl), or any combination thereof. Optionally substituted C 1-6 Examples of alkyl groups include, but are not limited to, e.g., C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl; deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.); halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; or-optionally substituted C 1-6 Alkylene-optionally substituted C 5-10 Aryl groups. -optionally substituted C 1-6 Alkylene-optionally substituted C 5-10 Examples of aryl groups include, but are not limited to, e.g., -optionally substituted C 1-6 Alkylene-optionally substituted C 6-10 Aryl, or-optionally substituted C 1-6 Alkylene-optionally substituted phenyl, wherein the aryl group is optionally substituted with a moiety selected from, for example, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluoro, chloro, bromo, iodo), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof, e.g. 1-4 or 2-3, substituted with one or more substituents; c 1-6 Alkylene is optionally substituted with a member selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl orT-butyl) halo C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof, e.g. 1-4 or 2-3.
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D) and formula (PBM-28-1D) 74 Each independently represents C 1-3 Alkylene (e.g. methylene, ethylene or propylene) or halogenated C 1-3 Alkylene (e.g., halomethylene, haloethylene, or halopropylene).
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D) and formula (PBM-28-1D) 73 Each independently represents optionally substituted C 3-6 Cycloalkyl, for example optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-or any group thereofAnd (5) combining.
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D) and formula (PBM-28-1D) 73 Each independently represents optionally substituted C 1-6 An alkyl group. Optionally substituted C 1-6 Substituents for alkyl groups include, but are not limited to, for example, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally substituted C 5-10 Aryl (e.g., optionally substituted phenyl or optionally substituted naphthyl), or any combination thereof. Optionally substituted C 1-6 Examples of alkyl groups include, but are not limited to, e.g., C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl; deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.); halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; or-optionally substituted C 1-6 Alkylene-optionally substituted C 5-10 Aryl groups. In some embodiments, -optionally substituted C 1-6 Alkylene-optionally substituted C 6-10 Examples of aryl groups include, but are not limited to, e.g., -optionally substituted C 1-6 Alkylene-optionally substituted C 6-10 Aryl, or-optionally substituted C 1-6 Alkylene-optionally substituted phenyl, wherein aryl or phenyl is optionally substituted with a moiety selected from, for example, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluoro, chloro, bromo, iodo), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof, e.g. 1-4 or 2-3, substituted with one or more substituents; c 1-6 Alkylene is optionally substituted with a member selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof, e.g. 1-4 or 2-3.
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D) and formula (PBM-28-1D) 73 Each independently represents cyclobutyl.
In some embodiments, PBM represents the structure of formula (PBM-28-1) below:
in some embodiments, PBM represents the structure of the following formula (PBM-51):
wherein the method comprises the steps of
R in formula (PBM-51) f2 Represents a bond, or R f2 represents-NH-R f3 -C (O) -, wherein the symbols represent the values associated with R f1 And R is f3 Represents optionally substituted C 3-8 Cycloalkyl;
(R 145 ) p53 1H-pyrrolo [2,3-b ] in the formula (PBM-51)]The pyridine ring is optionally substituted by p 53R 145 Substitution, each R 145 Each independently is cyano, halogen (e.g., fluorine, chlorine, bromine or iodine ) Hydroxyl, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、F 2 ClC-O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p53 represents an integer 0, 1, 2, 3, 4 or 5; and
(R 146 ) p54 the pyridine ring in the formula (PBM-51) is optionally substituted with p 54R 146 Substitution, each R 146 Each independently is cyano, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、F 2 ClC-O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) or NR b25 R b26 Wherein R is b25 、R b26 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl) or optionally substituted 4-to8-membered heterocyclyl (e.g., azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, diazepinyl, azetidinyl or diazinooctyl; and the 4-to 8-membered heterocyclyl is optionally substituted with C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, 3-methyl-2-oxoimidazolidin-1-yl, or any combination thereof, and p54 represents an integer 0, 1, 2, or 3.
In some embodiments, R in formula (PBM-51) f2 Representing a key.
In some embodiments, R in formula (PBM-51) f2 represents-NH-R f3 -C (O) -, wherein the symbols represent the values associated with R f1 And R is f3 Represents optionally substituted C 3-8 Cycloalkyl groups. In some embodiments, optionally substituted C 3-8 Examples of cycloalkyl groups include, but are not limited to, for example, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cycloheptyl, or optionally substituted cyclooctyl. In some embodiments, C 3-8 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-Or any combination thereof.
In some embodiments, (R) 145 ) p53 1H-pyrrolo [2,3-b ] in the formula (PBM-51)]The pyridine ring is optionally substituted by p 53R 145 Substitution, each R 145 Each independently is cyano, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、F 2 ClC-O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) and p53 represents an integer 0, 1, 2,3, 4 or 5.
In some embodiments, (R) 145 ) p53 1H-pyrrolo [2,3-b ] in the formula (PBM-51)]The pyridine ring being surrounded by p 53R' s 145 Substitution, wherein p53 represents an integer of 1, and R 145 Is cyano.
In some embodiments, (R) 146 ) p54 The pyridine ring in the formula (PBM-51) is optionally substituted with p 54R 146 Substitution, each R 146 Each independently is cyano, halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、F 2 ClC-O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-) or NR b25 R b26 Wherein R is b25 、R b26 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl) or optionally substituted 4-to 8-membered heterocyclyl (e.g., azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, diazepinyl, azepanyl, azacyclooctyl or diazinooctyl), and the 4-to 8-membered heterocyclyl is optionally substituted C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, 3-methyl-2-oxoimidazolidin-1-yl, or any combination thereof, and p54 represents an integer 0, 1, 2, or 3.
In some embodiments, (R) 146 ) p54 The pyridine ring in the formula (PBM-51) is substituted with p 54R 146 Substitution, wherein p54 represents an integer of 1, and R 146 Is NR b25 R b26 Wherein R is b25 Represents hydrogen and R b26 Represent C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl).
In some embodiments, PBM represents the structure of formula (PBM-51-1), formula (PBM-51-2), or formula (PBM-51-3):
in some embodiments, PBM represents the structure of the following formula (PBM-56):
wherein the method comprises the steps of
X in formula (PBM-56) 31 Represents N or CH;
(R 160 ) p62 x-containing in the formula (PBM-56) 31 Is substituted by p 62R 160 Substituted, each R 160 The radicals identical or different and each independently of the other denote halogen (e.g.fluorine, chlorine, bromine, iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. deuterated C 1-3 Alkyl radicals, e.g. CD 3 )、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy, and p62 represents an integer of 0, 1, 2, 3 or 4;
ring J represents a 5-to 15-membered heteroarylene group, (R) 161 ) p63 Represents the ring J is substituted by p 63R 161 Substituted, each R 161 The same or different and each independently represents halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxy, mercaptoRadicals, cyano radicals, amino radicals, nitro radicals, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. deuterated C 1-3 Alkyl radicals, e.g. CD 3 ) Hydroxy-substituted C 1-6 Alkyl (e.g. hydroxy-substituted C 1-4 Alkyl, e.g. hydroxypropyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-3 Alkoxy, such as trifluoromethoxy), and p63 represents an integer of 0, 1, 2 or 3;
in some embodiments, X 31 And represents N. In some embodiments, X 31 Represents CH.
In some embodiments, (R) 160 ) p62 X-containing in the formula (PBM-56) 31 Is substituted by p 62R 160 Substituted, each R 160 The radicals identical or different and each independently of the other denote halogen (e.g.fluorine, chlorine, bromine, iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. deuterated C 1-3 Alkyl radicals, e.g. CD 3 )、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy, p62 represents an integer 0, 1, 2, 3 or 4, and contains X 31 The aromatic ring of (a) is a pyridine ring or a benzene ring. In some embodiments, X is contained 31 The aromatic ring of (2) is pyridine ring, R 160 Represents F 3 C-, p62 represents an integer of 1.
In some embodiments, ring J represents a 5 to 15 membered heteroarylene, e.g., a 5 to 12 membered heteroarylene, or a 5 to 10 membered heteroarylene. In some embodiments, examples of ring J include, but are not limited to, benzothiazolyl, 2H-indazolyl, and benzoxazolyl. Ring J is optionally substituted with p 63R 161 Substituted, each R 161 The radicals identical or different and each independently of the other denote halogen (e.g.fluorine, chlorine, bromine, iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. deuterated C 1-3 Alkyl radicals, e.g. CD 3 ) Hydroxy-substituted C 1-6 Alkyl (e.g. hydroxy-substituted C 1-4 Alkyl groups, e.g. hydroxypropyl, hydroxyisopropyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-3 Alkoxy, such as trifluoromethoxy), and p63 represents an integer of 0, 1, 2 or 3. In some embodiments, R 161 Represents a hydroxypropyl group or a hydroxyisopropyl group, and p63 represents an integer of 1.
In some embodiments, the PBM represents the structure of formula (PBM-56-1), formula (PBM-56-2), formula (PBM-56-3), formula (PBM-56-4), formula (PBM-56-5), or formula (PBM-56-6) below:
in some embodiments, PBM-R f -a small molecule ligand representing KRAS.
In some embodiments, PBM represents the structure of the following formula (PBM-54):
wherein the method comprises the steps of
X in formula (PBM-54) 28 、X 29 And X 30 Each independently represents N or CH;
(R 154 ) p60 the naphthyl group in the formula (PBM-54) is optionally substituted with p 60R groups 154 Substituted, each R 154 Each independently represents halogen, hydroxy, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkyl or halo C 1-6 Alkyl, and p60 represents an integer of 0, 1, 2, 3, 4, 5, 6 or 7;
R 155 represents optionally substituted C 3-11 Cycloalkyl or optionally substituted 4-15 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; and
R 156 represents halogen, hydroxy, cyano, amino, mercapto, nitro, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkyl or halo C 1-6 An alkyl group.
In some embodiments, X in formula (PBM-54) 28 、X 29 And X 30 Each independently represents N or CH. In some embodiments, X in formula (PBM-54) 28 、X 29 And X 30 One of (a)Represents N, and the others each independently represent N or CH. In some embodiments, X in formula (PBM-54) 28 、X 29 And X 30 And the remaining one represents N or CH. In some embodiments, X in formula (PBM-54) 28 、X 29 And X 30 All represent N. In some embodiments, X in formula (PBM-54) 28 、X 29 And X 30 All represent CH.
In some embodiments, (R) 154 ) p60 The naphthyl group in the formula (PBM-54) is optionally substituted with p 60R groups 154 Substituted, each R 154 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, amino, mercapto, nitro, cyano, C 2-6 Alkynyl (e.g. ethynyl, propynyl, butynyl, pentynyl or hexynyl), C 2-6 Alkenyl (e.g. ethenyl, propenyl, butenyl, pentenyl or hexenyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy-, propoxy-, isopropoxy-, butoxy-, sec-butyloxy-or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p60 represents an integer of 0, 1, 2, 3, 4, 5, 6 or 7. In some embodiments, p60 represents an integer of 2, 3, or 4, and each R 154 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy or C 2-6 Alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl).
In some embodiments, R 155 Represents optionally substituted C 3-11 Cycloalkyl or optionally substituted containing 1-4 substituents selected from N, O and S4-15 membered heterocyclyl groups of heteroatoms. In some embodiments, optionally substituted C 3-11 Examples of cycloalkyl groups include, but are not limited to, for example, optionally substituted C 3-10 Cycloalkyl, or optionally substituted C 3-9 Cycloalkyl radicals, e.g. cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, noradamantane, adamantane, bornyl or norbornyl, where C 3-11 Cycloalkyl is optionally substituted with a member selected from the group consisting of, for example, deuterium, oxo, hydroxy, amino, mercapto, nitro, halogen (e.g., fluoro, chloro, bromo, iodo), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof, e.g. 1-4 or 2-3. In some embodiments, examples of optionally substituted 4-15 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S include, but are not limited to, for example, optionally substituted 4-12 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, or optionally substituted 4-11 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, for example, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, di Oxacyclohexyl, azepanyl, diazinoctyl, diazepinyl (e.g. 1, 4-diazepin-1-yl), diazepinyl, 6-azabicyclo [3.1.1 ]]Heptan-3-yl, 2, 5-diazabicyclo [2.2.1]Heptan-2-yl, 3, 6-diazabicyclo [3.1.1]Heptan-3-yl, 3-azabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octan-3-yl, 2, 5-diazabicyclo [2.2.2]Octan-2-yl, and azaspirocyclic groups (e.g. 3-azaspiro [5.5 ]]Undec-3-yl); the 4-15 membered heterocyclyl is optionally substituted with one or more, for example 1-4 or 2-3 substituents selected from the group consisting of: deuterium, oxo, hydroxy, amino, mercapto, nitro, halogen (e.g. fluoro, chloro, bromo, iodo), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof.
In some embodiments, R 156 Represents hydrogen, halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxy, C 2-6 Alkynyl (e.g. ethynyl, propynyl, butynyl, pentynyl or hexynyl), C 2-6 Alkenyl (e.g. ethenyl, propenyl, butenyl, pentenyl or hexenyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy-, propoxy-, isopropylOxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, PBM represents the structure of formula (PBM-54-1) below:
in some embodiments, PBM-R f -a small molecule ligand representing FGFR.
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D), and formula (PBM-28-1D) 74 Each independently represents a bond, i.e. R 74 Is not present.
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D) and formula (PBM-28-1D) 73 Each independently represents optionally substituted C 1-6 An alkyl group. Optionally substituted C 1-6 Substituents for alkyl groups include, but are not limited to, for example, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally substituted C 5-10 Aryl (e.g., optionally substituted phenyl or optionally substituted naphthyl), or any combination thereof. Optionally substituted C 1-6 Examples of alkyl groups include, but are not limited to, e.g., -optionally substituted C 1-6 Alkylene-optionally substituted C 6-10 Aryl groups. In some embodiments, -optionally substituted C 1-6 Alkylene-optionally substituted C 6-10 Examples of aryl groups include, but are not limited to, e.g., -optionally substituted C 1-6 Alkylene-optionally substituted C 6-10 Aryl, or-optionally substituted C 1-6 Alkylene-optionally substituted phenyl, wherein aryl or phenyl is optionally substituted with a moiety selected from, for example, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluoro, chloro, bromo, iodo), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy-, propoxy-, isopropoxy-, butoxy-, sec-butylA substituent group, or any combination thereof, such as 1-4 or 2-3; c 1-6 Alkylene is optionally substituted with a member selected from the group consisting of deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine, iodine), cyano, optionally deuterated C 1-4 Alkyl (e.g. optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-4 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or any combination thereof, e.g. 1-4 or 2-3.
In some embodiments, each R in formula (PBM-28-1A), formula (PBM-28-1B), formula (PBM-28-1C), formula (PBM-28-1D) and formula (PBM-28-1D) 73 Each independently represents
In some embodiments, PBM represents the structure of formula (PBM-28-2) below:
in some embodiments, PBM represents the structure of the following formula (PBM-29):
wherein the method comprises the steps of
R 75 Represent C 1-3 Alkylene (e.g. methylene, ethylene or propylene) or halogenated C 1-3 Alkylene (e.g., halomethylene, haloethylene, or halopropylene); and
R 76 represent C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or optionally substituted C 3-6 Cycloalkyl groups.
In some embodiments, R in formula (PBM-29) 76 Represents optionally substituted C 3-6 Cycloalkyl, for example optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-29-1):
in some embodiments, the PBM represents the structure of formula (PBM-30-1A), formula (PBM-30-1B), formula (PBM-30-1C), formula (PBM-30-1D), or formula (PBM-30-1E):
Wherein the method comprises the steps of
Each R in the formula (PBM-30-1A), the formula (PBM-30-1B), the formula (PBM-30-1C), the formula (PBM-30-1D) and the formula (PBM-30-1E) 77 Each independently represents C 1-3 Alkylene (e.g. methylene, ethylene or propylene) or halogenated C 1-3 Alkylene (e.g., halomethylene, haloethylene, or halopropylene);
R 78 represents hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 79 And R is 80 Identical or different and each independently represents hydrogen, optionally substituted C 1-10 Alkyl or optionally substituted C 3-6 Cycloalkyl; and
R 81 represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, each R in formula (PBM-30-1A), formula (PBM-30-1B), formula (PBM-30-1C), formula (PBM-30-1D) and formula (PBM-30-1E) 79 And R is 80 Identical or different and each independently represents hydrogen, optionally substituted C 1-10 Alkyl or optionally substituted C 3-6 Cycloalkyl groups. In some embodiments, optionally substituted C 1-10 Examples of alkyl groups include, but are not limited to, optionally substituted C 1-8 Alkyl, optionally substituted C 1-6 Alkyl, or optionally substituted C 1-4 An alkyl group. In some embodiments, C 1-10 Alkyl is optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) C's selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof. In some embodiments, optionally substituted C 3-6 Examples of cycloalkyl groups include, but are not limited to, for example, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, each R in formula (PBM-30-1A), formula (PBM-30-1B), formula (PBM-30-1C), formula (PBM-30-1D) and formula (PBM-30-1E) 79 Represents hydrogen, and R 80 Representation of
In some embodiments, PBM represents the structure of formula (PBM-30-1) below:
in some embodiments, PBM represents the structure of the following formula (PBM-31):
wherein the method comprises the steps of
X in the formula (PBM-31) 16 representing-S-or fragments
Wherein when X is 16 In the case of-S-, X is contained in the formula (PBM-31) 16 And heteroaryl of nitrogen atom is thiazolyl, and when X 16 Representing fragment->
When, in formula (PBM-31), X is contained 16 And heteroaryl of nitrogen atom is pyridinyl;
X 17 represents N or CH;
R 82 represents hydrogen or optionally substituted C 1-10 An alkyl group;
R 83 represents hydrogen, -C 1-3 Alkylene-optionally substituted 4-to 10-membered heterocyclyl, or optionally substituted 4-to 10-membered heterocyclyl; and
R 84 Represents hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, X in formula (PBM-31) 16 represents-S-, in the formula (PBM-31) containing X 16 And heteroaryl of nitrogen atom is thiazolyl.
In some embodiments, X in formula (PBM-31) 16 Representing segments
When, in formula (PBM-31), X is contained 16 And heteroaryl of nitrogen atom is pyridyl.
In some embodiments, R in formula (PBM-31) 82 Represents hydrogen or optionally substituted C 1-10 An alkyl group. In some embodiments, optionally substituted C 1-10 Examples of alkyl groups include, but are not limited to, optionally substituted C 1-8 Alkyl, optionally substituted C 1-6 Alkyl, or optionally substituted C 1-4 An alkyl group. In some embodiments, C 1-10 Alkyl is optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) C's selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R in formula (PBM-31) 83 Represents hydrogen, -C 1-3 Alkylene-optionally substituted 4-to 10-membered heterocyclyl, or optionally substituted 4-to 10-membered heterocyclyl. In some embodiments, each optionally substituted 4-to 10-membered heterocyclyl is, for example, a 4-to 10-membered (e.g., 4-to 9-membered, 4-to 8-membered, 5-to 7-membered, or 4-to 6-membered) monocyclic or bicyclic heterocyclyl containing one or more, for example, 1-4 or 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazacycloheptyl (e.g., 1, 4-diazacycloheptan-1-yl), azacyclooctyl, diazacyclooctyl, azabicyclo [ 3.1.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicycloRing [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-31-1A) or formula (PBM-31-1B) below:
wherein the method comprises the steps of
X 17 Represents N or CH;
R 82 represents hydrogen or optionally substituted C 1-10 An alkyl group;
R 83 represents hydrogen, -C 1-3 Alkylene-optionally substituted 4-to 10-membered heterocyclyl, or optionally substituted 4-to 10-membered heterocyclyl; and
R 84 represents hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenatedC 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, each R in formula (PBM-31-1A) and formula (PBM-31-1B) 82 Each independently represents hydrogen or optionally substituted C 1-10 An alkyl group. In some embodiments, optionally substituted C 1-10 Examples of alkyl groups include, but are not limited to, optionally substituted C 1-8 Alkyl, optionally substituted C 1-6 Alkyl, or optionally substituted C 1-4 An alkyl group. In some embodiments, C 1-10 Alkyl is optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) C's selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, each R in formula (PBM-31-1A) and formula (PBM-31-1B) 83 Each independently represents hydrogen, -C 1-3 Alkylene-optionally substituted 4-to 10-membered heterocyclyl, or optionally substituted 4-to 10-membered heterocyclyl. In some embodiments, each optionally substituted 4-to 10-membered heterocyclyl is, for example, a 4-to 10-membered (e.g., 4-to 9-, 4-to 8-membered, 5-to 7-membered, or 4-to 6-membered) monocyclic or bicyclic heterocyclyl containing one or more, for example, 1-4 or 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur, including, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanylRadicals, azepanyl radicals, diazepinyl radicals (e.g. 1, 4-diazepin-1-yl), azetidinyl radicals, diazinooctyl radicals, azabicyclo [3.1.1]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1 ]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-31-1) or formula (PBM-31-2) below:
in some embodiments, PBM represents the structure of the following formula (PBM-32):
wherein the method comprises the steps of
R in formula (PBM-32) 85 And R is 86 The same or different and each independently represents hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
R 87 representation-S (O) 2 NH 2 or-C (O) NH 2 。
In some embodiments, R in formula (PBM-32) 87 representation-S (O) 2 NH 2 。
In some embodiments, R in formula (PBM-32) 87 represents-C (O) NH 2 。
In some embodiments, PBM represents the structure of formula (PBM-32-1) or formula (PBM-32-2) below:
in some embodiments, PBM-R f -a small molecule ligand representing EZH 2.
In some embodiments, PBM represents the structure of the following formula (PBM-33):
wherein the method comprises the steps of
R 88 Represents hydrogen, hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups, e.g. methyl, ethyl,Propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 89 Represent C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; or (b)
R 88 And R is 89 Together with the corresponding carbon and nitrogen atoms to which they are each attached form an optionally substituted 4-to 6-membered heteroaryl ring or an optionally substituted 4-to 6-membered heterocycle;
R 90 represents optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,Sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 10-membered heterocyclyl;
(R 91 ) p27 the pyridin-2 (1H) -one ring in formula (PBM-33) is substituted with p 27R 91 Substituted, each R 91 The same or different and each independently represents hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p27 represents an integer of 1, 2 or 3;
ring F in the formula (PBM-33) represents an arylene group or a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 hetero atoms selected from N, O and SAn aryl group; (R) 92 ) p28 Represents the ring F optionally being substituted by p 28R 92 Substitution, each R 92 Identical or different and each independently represents deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
p28 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, R in formula (PBM-33) 88 Represents hydrogen, hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R in formula (PBM-33) 89 Represent C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, R in formula (PBM-33) 88 And R is 89 Together with the corresponding carbon and nitrogen atoms to which they are each attached form an optionally substituted 4-to 6-membered nitrogen containing heteroaryl ring or an optionally substituted 4-to 6-membered nitrogen containing heterocycle. In some embodiments, R in formula (PBM-33) 88 And R is 89 Together the following fragments are represented: -CH 2 -、-CH＝CH-、-CH＝N-、-N＝CH-、-N＝N-、-CH 2 -CH 2 -、-NH-CH 2 -, or-CH 2 -CH 2 -CH 2 -. In some embodiments, 4-to 6-membered nitrogen containing heterocycles include, but are not limited to, for example, those containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen and sulfurSub-4-to 6-membered (e.g., 4-, 5-, 6-membered) heterocycles. The 4-to 6-membered nitrogen-containing heterocyclic ring is condensed with the benzene ring in the formula (PBM-33) to form a condensed ring. The 4-to 6-membered nitrogen-containing heterocycle is optionally substituted with one or more (e.g., 1 to 4, 1 to 3, or 2) substituents selected from the group consisting of: halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, amino, cyano, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.). In some embodiments, R in formula (PBM-33) 90 Represents optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 10-membered heterocyclyl.
In some embodiments, R in formula (PBM-33) 90 Represents optionally substituted C 3-6 Cycloalkyl, for example optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R in formula (PBM-33) 90 Represents an optionally substituted 4-to 10-membered heterocyclic group. An optionally substituted 4-to 10-membered heterocyclyl is, for example, an optionally substituted 4-to 10-membered (e.g., 4-9, 4-8, 5-7, or 4-to 6-membered) monocyclic or bicyclic heterocyclyl containing one or more, for example 1-4 or 1, 2, 3 or 4, heteroatoms selected from nitrogen, oxygen and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ]]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1 ]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, a subject isThe 4-to 10-membered heterocyclic group is optionally substituted with C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, ring F in formula (PBM-33) represents an arylene group (e.g., C 5-20 Arylene group, C 5-15 Arylene group, C 5-10 Arylene group, or C 5-6 Arylene) or a 5-to 20-membered (e.g., 5-to 15-membered, 5-to 10-membered, 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, or 6-membered) monocyclic or bicyclic heteroarylene containing 1-4 (e.g., 1-3, or 1-2) heteroatoms selected from N, O and S. Examples of arylene groups include, but are not limited to, phenylene and naphthylene. Examples of heteroarylenes include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazolyl, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2,1,3 ] ]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinylene, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrroles]Thiazolylene and imidazo [2,1-b]Thiazole subunits. In some embodiments, the ring F is optionally substituted with p 28R 92 Substitution, each R 92 Identical toOr are different and each independently represents deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and p28 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, the PBM represents the following formula (PBM-33-1A), formula (PBM-33-1B), formula (PBM-33-1C), formula (PBM-33-1D), formula (PBM-33-1E), formula (PBM-33-1F), formula (PBM-33-1G), formula (PBM-33-1H), formula (PBM-33-1I), formula (PBM-33-1J), or formula (PBM-33-1K):
wherein the method comprises the steps of
R of various types 90 Each independently represents an optional substitutionC 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 10-membered heterocyclyl;
of the type (R) 91 ) p27 Each independently represents that the pyridin-2 (1H) -one ring of each formula is substituted with p 27R 91 Substituted, each R 91 The same or different and each independently represents hydroxy, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
Each of the various p27 s independently represents an integer 1, 2 or 3;
each of the various rings F independently represents an arylene group or a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S; (R) 92 ) p28 Represents the ring F optionally being substituted by p 28R 92 Substitution, each R 92 Identical or different and each independently represents deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and
each of the various p28 s independently represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, a compound of formula (PBM-33-1A), formula (PBM-33-1B), formula (PBM-33-1C), formula (PBM-33-1D), formula (PBM-33-1E), formula (PBM-33-1F), formula (PBM-33-1G), formula (PBM-33-1H), formula (PBM-33-1I), formula (PBM-33-1J), and formula (PBM-33-1K) 90 Each independently represents optionally substituted C 3-6 Cycloalkyl, for example optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, each R in formula (PBM-33-1A), formula (PBM-33-1B), formula (PBM-33-1C), formula (PBM-33-1D), formula (PBM-33-1E), formula (PBM-33-1F), formula (PBM-33-1G), formula (PBM-33-1H), formula (PBM-33-1I), formula (PBM-33-1J), and formula (PBM-33-1K) 90 Each independently represents an optionally substituted 4-to 10-membered heterocyclic group. An optionally substituted 4-to 10-membered heterocyclyl is, for example, an optionally substituted 4-to 10-membered (e.g., 4-9, 4-8, 5-7, or 4-to 6-membered) monocyclic or bicyclic heterocyclyl containing one or more, for example 1-4 or 1, 2, 3 or 4, heteroatoms selected from nitrogen, oxygen and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diaza-bisCyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 10-membered heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, each ring F in formula (PBM-33-1A), formula (PBM-33-1B), formula (PBM-33-1C), formula (PBM-33-1D), formula (PBM-33-1E), formula (PBM-33-1F), formula (PBM-33-1G), formula (PBM-33-1H), formula (PBM-33-1I), formula (PBM-33-1J), and formula (PBM-33-1K) each independently represents an arylene group (e.g., C) 5-20 Arylene group, C 5-15 Arylene group, C 5-10 Arylene group, or C 5-6 Arylene) or a 5-to 20-membered (e.g., 5-to 15-membered, 5-to 10-membered, 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, or 6-membered) monocyclic or bicyclic heteroarylene containing 1-4 (e.g., 1-3, or 1-2) heteroatoms selected from N, O and S. Examples of arylene groups include, but are not limited to, phenylene and naphthylene. Examples of heteroarylenes include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazolyl, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinylene, isoquinolyleneGroup, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ] ]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, 4H-fluoro [3,2-b ]]Pyrrolo [2,1-b ] pyrroles]Thiazolylene and imidazo [2,1-b]Thiazole subunits. In some embodiments, the ring F is optionally substituted with p 28R 92 Substitution, each R 92 Identical or different and each independently represents deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-); and p28 represents an integer of 0, 1,2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-33-1), formula (PBM-33-2), or formula (PBM-33-3):
In some embodiments, PBM-R f -a small molecule ligand representing NTRK.
In some embodiments, the PBM represents the structure of formula (PBM-34-1A), formula (PBM-34-1B), formula (PBM-34-1C), formula (PBM-34-1D), or formula (PBM-34-1E):
wherein the method comprises the steps of
Of the type (R) 93 ) p29 Each independently represents a benzene ring of each formula is substituted by p 29R 93 Substituted, each R 93 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p29 represents an integer of 1, 2, 3, 4 or 5;
r of various types 94 Each independently represents hydrogen, hydroxy, amino, cyano, halogen (e.g., fluoro, chloro, bromo or iodo), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
r of various types 95 Each independently represents NR b15 R b16 Wherein R is b15 、R b16 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl.
In some embodiments, each R in formula (PBM-34-1A), formula (PBM-34-1B), formula (PBM-34-1C), formula (PBM-34-1D), and formula (PBM-34-1E) b15 Each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl. In some embodiments, optionally substituted C 3-6 Examples of cycloalkyl groups include, but are not limited to, for example, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof. In some embodiments, an optionally substituted 4-to 8-membered heterocyclyl is, for example, an optionally substituted 4-to 8-membered (e.g., 4-7, 4-6, 5-7, or 5-6 membered) monocyclic or bicyclic heterocyclyl containing one or more, for example 1-4 or 1, 2, 3, or 4, heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, and dithianyl Nitrogen heterocyclic octyl. In some embodiments, the 4-to 8-membered heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, each R in formula (PBM-34-1A), formula (PBM-34-1B), formula (PBM-34-1C), formula (PBM-34-1D), and formula (PBM-34-1E) b16 Each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl. In some embodiments, optionally substituted C 3-6 Examples of cycloalkyl groups include, but are not limited to, for example, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof. In some embodiments, an optionally substituted 4-to 8-membered heterocyclyl is, for example, an optionally substituted 4-to 8-membered (e.g., 4-to 7-membered, 4-to 6-membered, 5-to 7-membered, or 5-to 6-membered) monocyclic or bicyclic heterocyclyl containing one or more, for example 1-4 or 1, 2, 3 or 4, heteroatoms selected from nitrogen, oxygen and sulfur, including, but not limited to, the following optionally substituted groupsAnd (3) ball: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ]]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1 ]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 8-membered heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, PBM represents the structure of formula (PBM-34-1) below:
in some embodiments, PBM represents the structure of the following formula (PBM-35):
wherein the method comprises the steps of
X in the formula (PBM-35) 18 、X 19 And X 20 Identical or different and each independently represents CH or N, wherein X 18 、X 19 And X 20 Different fromWhen N, and said containing X 18 、X 19 、X 20 And the six-membered ring of nitrogen atoms is optionally further substituted with 1 or 2 groups selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) or any combination thereof;
x in the formula (PBM-35) 21 And X 22 Identical or different and each independently represents C or N, wherein X 21 And X 22 Not both are N;
(R 96 ) p30 the benzene ring in the formula (PBM-35) is substituted with p 30R 96 Substituted, each R 96 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenSubstitute C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p30 represents an integer of 1, 2, 3, 4 or 5;
(R 97 ) p31 the tetrahydropyrrole ring in formula (PBM-35) is optionally substituted with p 31R 97 Substituted, each R 97 The same or different and each independently represents hydrogen, hydroxy, amino, cyano, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p31 represents an integer of 0, 1, 2, 3, 4, 5 or 6; and
R 98 、R 99 、R 100 the same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, e.gSuch as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, X in formula (PBM-35) 18 、X 19 And X 20 Represents CH.
In some embodiments, X in formula (PBM-35) 18 Represents N, and X 19 And X 20 Represents CH.
In some embodiments, X in formula (PBM-35) 19 Represents N, and X 18 And X 20 Represents CH.
In some embodiments, X in formula (PBM-35) 20 Represents N, and X 18 And X 19 Represents CH.
In some embodiments, X in formula (PBM-35) 20 Represents CH and X 18 And X 20 And represents N.
In some embodiments, X in formula (PBM-35) 21 Represents C and X 22 And represents N.
In some embodiments, X in formula (PBM-35) 21 Represents N, and X 22 And represents C.
In some embodiments, the PBM represents the following formula (PBM-35-1A), formula (PBM-35-1B), formula (PBM-35-1C), formula (PBM-35-1D), formula (PBM-35-1E), formula (PBM-35-1F), formula (PBM-35-1G), formula (PBM-35-1H), formula (PBM-35-1I), or formula (PBM-35-1J):
wherein the method comprises the steps of
Of the type (R) 96 ) p30 Each independently represents a benzene ring substituted by p 30R 96 Substituted, each R 96 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p30 represents an integer of 1, 2, 3, 4 or 5;
of the type (R) 97 ) p31 The tetrahydropyrrole rings in formula (PBM-35) are optionally substituted with p 31R' s 97 Substituted, each R 97 The same or different and each independently represents hydrogen, hydroxy, amino, cyano, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, e.g. methylEthyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p31 represents an integer of 0, 1, 2, 3, 4, 5 or 6; and
r of various types 98 、R 99 、R 100 Each independently the same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, the PBM represents the structure of formula (PBM-35-1), formula (PBM-35-2), formula (PBM-35-3), formula (PBM-35-4), formula (PBM-35-5), or formula (PBM-35-6) below:
in some embodiments, PBM-R f -a small molecule ligand representing SHP 2.
In some embodiments, PBM represents the structure of the following formula (PBM-36):
wherein the method comprises the steps of
X in the formula (PBM-36) 23 Represents CH or N;
R 101 represents a bond or-S-;
R 102 represents a bond or an optionally substituted 4-to 15-membered nitrogen-containing heterocyclic group;
R 103 represents a bond, halogen (e.g. fluorine, chlorine, bromine or iodine), amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 15-membered nitrogen containing heterocyclyl;
wherein R is 102 And R is 103 Not both being bonds, and R 102 And R is 103 Wherein only one of R is a bond 102 When the bond is represented, R is the same as 102 The ring carbon atoms to which they are attached being directly attached R f And when R 103 When the bond is represented, R is the same as 103 The ring carbon atoms to which they are attached being directly attached R f ；
(R 104 ) p32 The six-membered ring in the formula (PBM-36) is optionally substituted with p 32R' s 104 Substituted, each R 104 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p32 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, R in formula (PBM-36) 102 Represents a bond, and R 103 Represents halogen (e.g. fluorine, chlorine, bromine or iodine), amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 An alkyl group, a hydroxyl group,such as CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 15-membered nitrogen containing heterocyclyl. In some embodiments, an optionally substituted 4-to 15-membered nitrogen-containing heterocyclyl is, for example, an optionally substituted 4-to 15-membered (e.g., 4-10 membered, 4-9 membered, 4-8 membered, 5-7 membered, or 4-6 membered) monocyclic or bicyclic heterocyclyl containing one nitrogen atom and optionally containing one or more (e.g., 1-3, or 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 15-membered nitrogen containing heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluoro, chloro, bromo or iodo), cyano, optionally deuterated 1-6 Alkyl (e.g. optionally perdeuterated C 1-6 Alkyl, optionally perdeuterated C 1-5 Alkyl or optionally perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, R in formula (PBM-36) 103 Represents a bond, and R 102 Represents an optionally substituted 4-to 15-membered nitrogen-containing heterocyclic group. In some embodiments, the optionally substituted 4-to 15-membered nitrogen-containing heterocyclyl is, for example, an optionally substituted 4-to 15-membered (e.g., 4-10-, 4-9-, 4-8-, 5-7-, or 4-6-membered) monocyclic or bicyclic heterocyclyl containing one nitrogen atom and optionally containing one or more (e.g., 1-3, or 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, and sulfur, including but not limited toThe following optionally substituted groups are limited: azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 15-membered nitrogen containing heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluoro, chloro, bromo or iodo), cyano, optionally deuterated 1-6 Alkyl (e.g. optionally perdeuterated C 1-6 Alkyl, optionally perdeuterated C 1-5 Alkyl or optionally perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, R in formula (PBM-36) 101 Representing a key.
In some embodiments, R in formula (PBM-36) 101 represents-S-.
In some embodiments, X in formula (PBM-36) 23 Represents CH.
In some embodiments, X in formula (PBM-36) 23 And represents N.
In some embodiments, the PBM represents the following formula (PBM-36-1A), formula (PBM-36-1B), formula (PBM-36-1C), formula (PBM-36-1D), formula (PBM-36-1E), formula (PBM-36-1F), formula (PBM-36-1G), or formula (PBM-36-1H):
wherein the method comprises the steps of
R of various types 102 Each independently represents an optionally substituted 4-to 15-membered nitrogen-containing heterocyclic group;
r of various types 103 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 15-membered nitrogen containing heterocyclyl;
of the type (R) 104 ) p32 Each independently represents a six-membered ring of the formula optionally substituted by p 32R 104 Substituted, each R 104 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p32 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, formula (PBM-36-1E), formula (PBM-36-1F),Each R in the formula (PBM-36-1G), and the formula (PBM-36-1H) 103 Each independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or an optionally substituted 4-to 15-membered nitrogen containing heterocyclyl. In some embodiments, an optionally substituted 4-to 15-membered nitrogen-containing heterocyclyl is, for example, an optionally substituted 4-to 15-membered (e.g., 4-10 membered, 4-9 membered, 4-8 membered, 5-7 membered, or 4-6 membered) monocyclic or bicyclic heterocyclyl containing one nitrogen atom and optionally containing one or more (e.g., 1-3, or 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ]]Heptyl and azabicyclo [2.2.1 ]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 15-membered nitrogen containing heterocyclyl is optionally selected from deuterium, hydroxy, aminoMercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally perdeuterated C 1-6 Alkyl, optionally perdeuterated C 1-5 Alkyl or optionally perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In one placeIn some embodiments, each R in formula (PBM-36-1A), formula (PBM-36-1B), formula (PBM-36-1C), and formula (PBM-36-1D) 102 Each independently represents an optionally substituted 4-to 15-membered nitrogen-containing heterocyclic group. In some embodiments, an optionally substituted 4-to 15-membered nitrogen-containing heterocyclyl is, for example, an optionally substituted 4-to 15-membered (e.g., 4-10 membered, 4-9 membered, 4-8 membered, 5-7 membered, or 4-6 membered) monocyclic or bicyclic heterocyclyl containing one nitrogen atom and optionally containing one or more (e.g., 1-3, or 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 15-membered nitrogen containing heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluoro, chloro, bromo or iodo), cyano, optionally deuterated 1-6 Alkyl (e.g. optionally perdeuterated C 1-6 Alkyl, optionally perdeuterated C 1-5 Alkyl or optionally perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-5 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g. optionally perdeuterated cyclopropyl, optionally perdeuterated ring)Butyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, the PBM represents the structure of formula (PBM-36-1), formula (PBM-36-2), formula (PBM-36-3), formula (PBM-36-4), formula (PBM-36-5), formula (PBM-36-6), formula (PBM-36-7), formula (PBM-36-8), or formula (PBM-36-9) below.
In some embodiments, PBM represents the structure of formula (PBM-9-1C):
wherein the method comprises the steps of
X of the formula (PBM-9) 1 Represents N or CR b7 Wherein R is b7 Is hydrogen or represents amino, and X 3 Represents CH or N;
(R 20 ) p10 the benzene ring in the formula (PBM-9-1C) is substituted with p 10R 20 Substituted, each R 20 Identical or different and each independently represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, -C 1-3 alkylene-C (O) NH-heteroaryl or halogen (e.g., fluorine, chlorine, bromine or iodine), each of said aryl and heteroaryl groups independently being optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R' s b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
p10 represents an integer of 1, 2, 3 or 4;
R 21 represents deuterium, hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy); and
R 22 represents hydrogen, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, or amino.
In some embodiments, R in formula (PBM-9-1C) 20 represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, wherein the aryl group may be optionally substituted C 6-10 Aryl groups, including but not limited to, for example, phenyl or naphthyl, heteroaryl groups may be optionally substituted 5-to 14-membered monocyclic or bicyclic aromatic ring groups containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. In a sub-embodiment, R 20 represents-O-phenyl or-O-naphthyl, the phenyl or naphthyl optionally being substituted by one or more (e.g. 1-5, such as 1, 2, 3, 4 or 5) R' s b8 Substitution, each R b8 Identical or different and are each independently deuteriumHalogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, R 20 represents-O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, or-C 1-3 alkylene-C (O) NH-heteroaryl, optionally substituted with one or more (e.g., 1-5, such as 1, 2, 3, 4 or 5) R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl radicalHalogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy or halo C 1-3 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-). In a sub-embodiment, examples of heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b ]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, or imidazoleAnd [2,1-b ]]Thiazolyl.
In some embodiments, PBM represents the structure of formula (PBM-9-4) or formula (PBM-9-5) below:
in some embodiments, PBM-R f -a small molecule ligand representing PARP.
In some embodiments, the PBM represents the structure of formula (PBM-37-1A), formula (PBM-37-1B), formula (PBM-37-1C), formula (PBM-37-1D), or formula (PBM-37-1E):
wherein the method comprises the steps of
Of the type (R) 105 ) p33 Each independently represents a benzene ring of the formula optionally substituted by p 33R 105 Substituted, each R 105 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p33 represents an integer of 1, 2, 3 or 4;
Of the type (R) 106 ) p34 Each independently represents a phthalazinone ring of the formula optionally substituted by p 34R 106 Substituted, each R 106 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p34 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-37-1):
in some embodiments, the PBM represents the structure of formula (PBM-38-1A), formula (PBM-38-1B), formula (PBM-38-1C), formula (PBM-38-1D), or formula (PBM-38-1E):
wherein the method comprises the steps of
Of the type (R) 107 ) p35 Each independently represents a 2H-indazole ring of the formula optionally substituted with p 35R 107 Substituted, each R 107 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p35 represents an integer of 0, 1, 2 or 3;
of the type (R) 108 ) p36 Each independently represents a benzene ring of the formula optionally substituted by p 36R 108 Substituted, each R 108 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy groups, e.g. methoxy, ethoxyPropoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p36 represents an integer of 0, 1, 2 or 3.
In some embodiments, PBM represents the structure of formula (PBM-38-1) below:
in some embodiments, the PBM represents the structure of formula (PBM-39-1A), formula (PBM-39-1B), formula (PBM-39-1C), formula (PBM-39-1D), or formula (PBM-39-1E):
wherein the method comprises the steps of
Of the type (R) 109 ) p37 Each independently represents a 2H-indazole ring of the formula optionally substituted with p 37R 109 Substituted, each R 109 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy groups, e.g. methoxy, ethoxy, propoxy,Isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p37 represents an integer of 0, 1, 2 or 3;
of the type (R) 110 ) p38 Each independently represents a benzene ring of the formula optionally substituted by p 38R 110 Substituted, each R 110 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p38 represents an integer of 0, 1, 2 or 3.
In some embodiments, PBM represents the structure of formula (PBM-39-1) below:
in some embodiments, the PBM represents the structure of formula (PBM-40-1A), formula (PBM-40-1B), formula (PBM-40-1C), formula (PBM-40-1D), or formula (PBM-40-1E):
wherein the method comprises the steps of
Of the type (R) 111 ) p39 Each independently represents a benzene ring of the formula optionally substituted by p 39R 111 Substituted, each R 111 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
p39 represents an integer of 0, 1, 2, 3 or 4; and
R 112 、R 113 、R 114 the same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, PBM represents the structure of formula (PBM-40-1) below:
In some embodiments, the PBM represents the structure of formula (PBM-41-1A), formula (PBM-41-1B), formula (PBM-41-1C), formula (PBM-41-1D), or formula (PBM-41-1E):
wherein the method comprises the steps of
R 115 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 116 、R 117 、R 118 The same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
Of the type (R) 119 ) p40 Each independently represents a benzene ring of the formula optionally substituted by p 40R 119 Substituted, each R 119 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy groups, e.g. methoxy, ethoxyA radical, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy group), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p40 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-41-1) below:
in some embodiments, PBM-R f -a small molecule ligand representing STAT 3.
In some embodiments, PBM represents the structure of the following formula (PBM-42):
wherein the method comprises the steps of
R 120 、R 121 The same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-3 Alkyl (e.g. methyl, ethyl or propyl), or halogenated C 1-3 Alkyl (e.g. halogenated C) 1-2 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 122 Represents bond, hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
R 123 The structure of the following formula is shown:
wherein R is 124 Represents a bond or hydrogen; (R) 125 ) p41 Represents the benzene ring optionally substituted by p 41R 125 Substituted, each R 125 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p41 represents an integer 0, 1, 2, 3 or 4; or (b)
R 123 The structure of the following formula is shown:
wherein (R) 126 ) p42 Represents the benzene ring optionally substituted by p 42R 126 Substituted, each R 126 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p42 represents an integer 0, 1, 2, 3, 4 or 5; and
wherein R is 122 And R is 124 Not both the key and the key are used,and R is 122 And R is 124 Wherein when R represents a bond 122 When the bond is represented, R is the same as 122 The ring nitrogen atom being bound directly to R f And when R 124 When the bond is represented, R is the same as 124 The ring carbon atoms to which they are attached being directly attached R f 。
In some embodiments, R in formula (PBM-42) 122 Is a key. In this case with R 122 The ring nitrogen atom being bound directly to R f 。R 123 The structure of the following formula is shown:
wherein R is 124 Represents hydrogen, (R) 125 ) p41 Represents the benzene ring optionally substituted by p 41R 125 Substituted, each R 125 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p41 represents an integer of 0, 1, 2, 3 or 4.
In one placeIn some embodiments, R in formula (PBM-42) 122 Is a key. In this case with R 122 The ring nitrogen atom being bound directly to R f 。R 123 The structure of the following formula is shown:
wherein (R) 126 ) p42 Represents the benzene ring optionally substituted by p 42R 126 Substituted, each R 126 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p42 represents an integer 0, 1, 2, 3, 4 or 5.
In some embodiments, when R 123 The structure of the following formula is shown:
wherein R is 124 Representing a bond (i.e. with R 124 The ring carbon atoms to which they are attached being directly attached R f )，(R 125 ) p41 R as defined above 122 Represents hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)。
In some embodiments, PBM represents the structure of formula (PBM-42-1A):
wherein the method comprises the steps of
R 120 、R 121 The same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-3 Alkyl (e.g. methyl, ethyl or propyl), or halogenated C 1-3 Alkyl (e.g. halogenated C) 1-2 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
(R 125 ) p41 represents the benzene ring optionally substituted by p 41R 125 Substituted, each R 125 Are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g. fluorine, Chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p41 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-42-1B):
wherein the method comprises the steps of
R 120 、R 121 The same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-3 Alkyl (e.g. methyl, ethyl or propyl), or halogenated C 1-3 Alkyl (e.g. halogenated C) 1-2 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
(R 126 ) p42 represents the benzene ring optionally substituted by p 42R 126 Substituted, each R 126 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p42 represents an integer 0, 1, 2, 3, 4 or 5.
In some embodiments, the PBM represents the following formula (PBM-42-1C), formula (PBM-42-1D), formula (PBM-42-1E), formula (PBM-42-1F), or formula (PBM-42-1G):
wherein the method comprises the steps of
R 120 、R 121 The same or different and each independently represents hydrogen, halogen (e.g. fluorine, chlorine, bromine or iodine), C 1-3 Alkyl (e.g. methyl, ethyl or propyl), or halogenated C 1-3 Alkyl (e.g. halogenated C) 1-2 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
(R 125 ) p41 represents the benzene ring optionally substituted by p 41R 125 Substituted, each R 125 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl or halo C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), and p41 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-42-1) or formula (PBM-42-2) below:
in some embodiments, PBM represents the structure of formula (PBM-43-1A) or formula (PBM-43-1B) below:
wherein the method comprises the steps of
Of the type (R) 127 ) p43 Each independently represents a benzene ring of the formula optionally substituted by p 43R 127 Substituted, each R 127 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p43 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, PBM represents the structure of formula (PBM-43-1) below:
in some embodiments, PBM-R f -a small molecule ligand representing FLT 3.
In some embodiments, the PBM represents the structure of formula (PBM-45-1A), formula (PBM-45-1B), formula (PBM-45-1C), formula (PBM-45-1D), or formula (PBM-45-1E):
wherein the method comprises the steps of
R 131 Represent C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), or R 131 Represents hydrogen;
R 132 represent C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl (e.g. optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), optionally substituted 4-to 8-membered nitrogen-containing heterocyclyl or NR b11 R b12 Wherein R is b11 、R b12 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl orHexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or optionally substituted 4-to 8-membered heterocyclyl;
(R 133 ) p46 the benzene ring in the formula (PBM-45-1A), the formula (PBM-45-1B), the formula (PBM-45-1C), the formula (PBM-45-1D), or the formula (PBM-45-1E) is optionally substituted with p 46R 133 Substituted, each R 133 The radicals are identical or different and each independently represents hydroxy, amino, cyano, halogen (e.g.fluorine, chlorine, bromine or iodine), C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) -; and
p46 represents an integer of 0, 1, 2, 3 or 4.
In some embodiments, R 131 Represents ethyl.
In some embodiments, R 131 Represents hydrogen.
In some embodiments, R 132 Represents NR b11 R b12 Wherein R is b11 、R b12 Identical or different and each independently represents hydrogen, C 1-6 Alkyl (e.g. C 1-4 Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl radicalButyl, pentyl or hexyl), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.), or optionally substituted 4-to 8-membered heterocyclyl. In some embodiments, an optionally substituted 4-to 8-membered heterocyclyl is, for example, an optionally substituted 4-to 8-membered (e.g., 4-7, 4-6, 5-7, or 5-6 membered) monocyclic or bicyclic heterocyclyl containing one or more, for example 1-4 or 1, 2, 3, or 4, heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 8-membered heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof. In some embodiments, R 132 Represents NR b11 R b12 Wherein R is b11 Represents hydrogen, R b12 Represents an optionally substituted tetrahydropyranyl group, said tetrahydropyranyl group being optionally substituted by a group selected from deuterium, hydroxy, amino, mercapto, nitroRadicals, halogens, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R 132 Represents optionally substituted C 3-6 Cycloalkyl, for example optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl. In some embodiments, C 3-6 Cycloalkyl groups are optionally substituted with one or more (e.g., 1-3, 1, 2 or 3) substituents selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R 132 Represents an optionally substituted 4-to 8-membered heterocyclic group. In some embodiments, an optionally substituted 4-to 8-membered heterocyclyl is, for example, an optionally substituted 4-to 8-membered (e.g., 4-7, 4-6, 5-7, or 5-6 membered) monocyclic or bicyclic heterocyclyl containing one or more, for example 1-4 or 1, 2, 3, or 4, heteroatoms selected from nitrogen, oxygen, and sulfur, including, but not limited to, the following optionally substituted groups: azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ] ]Heptyl and azabicyclo [2.2.1]Heptyl and azaBicyclo [3.2.1]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl), and diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). In some embodiments, the 4-to 8-membered heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, 3-methyl-2-oxoimidazolidin-1-yl, or any combination thereof. In some embodiments, R 132 Represents piperidinyl optionally substituted by 3-methyl-2-oxoimidazolidin-1-yl.
In some embodiments, p46 represents an integer of 0. In some embodiments, p46 represents 1, and R 133 Represents methoxy.
In some embodiments, PBM represents the structure of formula (PBM-45-1) below:
In some embodiments, PBM-R f -a small molecule ligand representing BCL-2.
In some embodiments, PBM represents the structure of formula (PBM-47-1) or formula (PBM-47-2) below:
in some embodiments, PBM-R f -a small molecule ligand representing ALK 2.
In some embodiments, PBM represents the structure of the following formula (PBM-48):
ring H in formula (PBM-48) represents C 6-10 Arylene or C 5-10 Heteroarylene (R) 137 ) p49 Represents the ring H optionally being substituted by p 49R' s 137 Substitution, each R 137 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)；
p49 represents an integer of 0, 1, 2, 3 or 4; and
R 136 Represents an optionally substituted 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1 to 4 heteroatoms selected from N, O and S, optionally substituted by a member selected from hydroxy, amino, cyano, halogen (exampleSuch as fluorine, chlorine, bromine, iodine), C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) substituent.
In some embodiments, the ring H in formula (PBM-48) represents phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinyl, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuran, isobenzofuran, benzothiophenylene, indazoylene, benzimidazole, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2,1,3 ] ]Oxadiazole subunits and benzo [2,1,3 ]]Thiadiazole subunit, benzo [1,2,3]Thiadiazole subunits, quinolinylene, isoquinolylene, naphthyridine subunits, cinnolinyl, quinazolinylene, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, pyrrolo [2,1-b]Thiazolylene, imidazo [2,1-b]Thiazolylene or imidazo [1,2-b]Pyridazine subunits. In some embodiments, ring H is optionally substituted with p49R is a number of 137 Substitution, wherein p49 represents an integer 0, 1,2,3 or 4, and each R 137 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, ring H in formula (PBM-48) represents phenylene, which is optionally substituted with p49 Rs 137 Substitution, wherein p49 represents an integer 0, 1, 2, 3 or 4, and each R 137 Identical or different and are each independently deuterium, halogen (e.g. fluorine, chlorine, bromine, iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-)。
In some embodiments, R in formula (PBM-48) 136 Represents an optionally substituted 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S. In some embodiments, R 136 Represents furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl, imidazo [2,1-b]Thiazolyl or imidazoleAnd [1,2-b ]]And a pyridazinyl group. In some embodiments, R 136 Optionally via one or more (e.g. 1-6, such as 1,2,3, 4, 5 or 6) groups selected from hydroxy, amino, cyano, halogen (e.g. fluoro, chloro, bromo, iodo), C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) substituent.
In some embodiments, R in formula (PBM-48) 136 Represents quinolinyl, which is optionally substituted by one or more (e.g. 1 to 6, such as 1, 2, 3, 4, 5 or 6) groups selected from hydroxy, amino, cyano, halogen (e.g. fluoro, chloro, bromo, iodo), C 1-6 Alkyl (e.g. C 1-4 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc.) or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-) substituent.
In some embodiments, PBM represents the structure of formula (PBM-48-1) or formula (PBM-48-2) below:
in some embodiments, PBM-R f -a small molecule ligand representing SOS 1.
In some embodiments, PBM represents the structure of the following formula (PBM-50):
wherein the method comprises the steps of
(R 143 ) p51 The benzene ring in the formula (PBM-50) is optionally substituted with p 51R 143 Substitution, each R 143 Each independently is halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy groups such as trifluoromethoxy);
p51 represents an integer of 0, 1, 2, 3, 4 or 5;
R 142 representation H, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), or halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
(R 144 ) p52 The quinazoline ring in formula (PBM-50) is optionally substituted with p 52R 144 Substitution, each R 144 Each independently is halogen (e.g., fluorine, chlorine, bromine or iodine), hydroxy, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 Alkyl or perdeuterated C 1-4 Alkyl radicals, e.g. CD 3 、CD 3 CD 2 -、CD 3 CD 2 CD 2 -etc., C 1-6 Alkoxy (e.g. C 1-5 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or haloC 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy groups such as trifluoromethoxy); and
p52 represents an integer of 1, 2, or 3.
In some embodiments, p51 represents an integer of 0, 1, 2, 3, 4, or 5. In some sub-embodiments, p51 represents an integer of 2.
In some embodiments, p52 represents an integer of 1, 2, or 3. In some sub-embodiments, p52 represents an integer of 1.
In some embodiments, PBM represents the structure of formula (PBM-50-1) or formula (PBM-50-2) below:
in some embodiments, R of formula (II) f Represents a bond, -O-, -NHC (O) -, -C (O) NH-, or-NH-.
In some embodiments, R of formula (II) f The structure of the following formula is shown:
-N(R g )-、-NHC(O)-C 1-6 alkylene group-W 5 -*、-NHC(O)-C 2-6 alkenylene-W 5 -*、-C(O)NH-C 1-6 Alkylene group-W 5 -*、-C(O)NH-C 2-6 alkenylene-W 5 -*、-NHC(O)-W 5 -*、-C(O)NH-W 5 -*、-O-C 1-6 Alkylene group-W 5 -*、-O-C 2-6 alkenylene-W 5 -*、-O-W 5 -*、-O-C 1-6 alkylene-N (R) i )-*、-O-C 2-6 alkenylene-N (R) i )-*、-N(R g )-C 1-6 alkylene-N (R) i )-*、-N(R g )-C 2-6 alkenylene-N (R) i )-*、-W 5 -、-W 5 -N(R g )-*、-N(R g )-W 5 -*、-N(R g )-W 5 -N(R i )-*、-C 1-6 Alkylene group-W 5 -*、-C 2-6 alkenylene-W 5 -*、-C 1-6 alkylene-C (O) -W 5 -*、-C 2-6 alkenylene-C (O) -W 5 -*、-C(O)-W 5 -*、-C 1-6 alkylene-C (O) NH-C 1-6 Alkylene group-W 5 -*、-C 1-6 alkylene-C (O) NH-C 2-6 alkenylene-W 5 -*、-C 2-6 alkenylene-C (O) NH-C 1-6 Alkylene group-W 5 -*、-C 2-6 alkenylene-C (O) NH-C 2-6 alkenylene-W 5 -*、-C 1-6 alkylene-NHC (O) -C 1-6 Alkylene group-W 5 -*、-C 1-6 alkylene-NHC (O) -C 2-6 alkenylene-W 5 -*、-C 2-6 alkenylene-NHC (O) -C 1-6 Alkylene group-W 5 -*、-C 2-6 alkenylene-NHC (O) -C 2-6 alkenylene-W 5 -*、-C 1-6 alkylene-C (O) NH-, -C 2-6 alkenylene-C (O) NH-, -C 1-6 alkylene-NHC (O) -, -C 2-6 alkenylene-NHC (O) -, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 1-6 alkylene-N (R) i )-*、-C 2-6 alkenylene-N (R) i ) -, or
Wherein R is g And R is i Each independently represents hydrogen or C 1-6 Alkyl, and the C 1-6 Alkylene and said C 2-6 Alkenylene is optionally substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Substituents of alkoxy groups or any combination thereof;
wherein the radical W 5 The structure of the following formula is shown:
wherein each ring W 6 Identical or different and each independently represents a nitrogen-containing heterocyclylene group, t1 represents an integer 1 or 2, (R) a2 ) m2
Representation ofEach ring W 6 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6
Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and the C 1-6 Alkylene and said C 2-6 Alkenylene is optionally substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 An alkoxy group or any combination thereof, and m2 represents an integer of 0 to 20;
each ring W 7 Identical or different and each independently represents a nitrogen-containing heterocyclylene, arylene, or heteroarylene group, t2 represents an integer 0 or 1, (R) a3 ) m3 Representing each ring W 7 Independently optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl group,
C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein
R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m3 represents an integer of 0 to 20; to be used forAnd
The symbol x represents the connection point to LIN.
In some embodiments, R g Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), and the said C 1-6 Alkylene and said C 2-6 Alkenylene is optionally substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Substituents of alkoxy groups or any combination thereof;
in some embodiments, R i Represents hydrogen or C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl).
In some embodiments, t1 represents an integer of 1.
In some embodiments, t1 represents an integer 2.
In some embodiments, each ring W 6 And are identical or different and each independently represents a 4-to 20-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) nitrogen-containing heterocyclic group, e.g., a 4-to 20-membered (e.g., 4-to 15-, 4-to 12-, 4-to 11-, 4-to 10-, 4-to 9-, 4-to 8-, 4-to 7-, 4-to 6-, 5-to 15-, or 5-to 9-membered) heterocyclic group containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of nitrogen-containing heterocycles include, but are not limited to, for example, piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazepinyl, azepanyl, diazepinyl, azabicyclo [3.1.1 ] ]Heptanylene and azabicyclo [2.2.1]Heptanylene and azabicyclo [3.2.1]Octane subunit, azabicyclo[2.2.2]Octane subunit, diazabicyclo [3.1.1]Heptanylene and diazabicyclo [2.2.1]Heptanylene and diazabicyclo [3.2.1]Octane subunit, diazabicyclo [2.2.2]Octane subunit, 3-azaspiro [5.5 ]]Undecylenic subunit, 8-azaspiro [4.5 ]]Decane subunit, 2-oxa-8-azaspiro [4.5 ]]Decane subunit, or 3-methyl-2-oxa-8-azaspiro [4.5 ]]Decane subunit. Each ring W 6 Are each independently optionally substituted with m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally halogenated C 1-6 Alkyl (e.g. optionally halogenated C 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, tert-butyloxy, pentoxy, or hexyloxy), halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 12a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl or propyl) and the C 1-6 Alkylene and said C 2-6 Alkenylene groups optionally substituted with one or more groups selected from halogen (e.g. fluoro, chloro, bromo or iodo), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-3 Alkyl (e.g. halogenated C) 1-2 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-3 Alkoxy (e.g., methoxy, ethoxy, propoxy, or isopropoxy), halo C 1-3 Alkoxy (e.g. halogenated C 1-2 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-), or any combination thereof. m2 represents an integer of 0 to 20, for example, an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 20. The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block.
In some embodiments, each ring W 6 The same or different and each independently represents the following optionally substituted groups:
each ring W 6 Are each independently optionally substituted with m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally halogenated C 1-6 Alkyl (e.g. optionally halogenated C 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, tert-butyloxy, pentoxy, or hexyloxy), halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 12a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl or propyl) and the C 1-6 Alkylene and said C 2-6 Alkenylene groups optionally substituted with one or more groups selected from halogen (e.g. fluoro, chloro, bromo or iodo), hydroxy, mercapto, cyano, aminoNitro, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 Alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-3 Alkyl (e.g. halogenated C) 1-2 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-3 Alkoxy (e.g., methoxy, ethoxy, propoxy, or isopropoxy), halo C 1-3 Alkoxy (e.g. halogenated C 1-2 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-), or any combination thereof. m2 represents an integer of 0 to 20, for example, an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 20. The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block.
In some embodiments, each ring W 7 And are identical or different and each independently represents a 4-to 15-membered (e.g., 4-to 12-membered, 4-11-membered, 4-10-membered, 4-to 9-membered, 4-to 8-membered, 4-to 7-membered, 4-to 6-membered, 5-to 15-membered, or 5-to 9-membered) nitrogen-containing heterocyclylene, a 6-to 10-membered (e.g., 6-to 8-membered or 6-to 7-membered) arylene, or a 5-to 10-membered (e.g., 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, or 5-to 6-membered) heteroarylene. In some embodiments, a 4-to 15-membered nitrogen-containing heterocyclylene is a 4-to 15-membered (e.g., 4-to 12-membered, 4-to 11-membered, 4-to 10-membered, 4-to 9-membered, 4-to 8-membered, 4-to 7-membered, 4-to 6-membered, 5-to 15-membered, or 5-to 9-membered) heterocyclylene containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of 4-to 15-membered nitrogen-containing heterocyclylene groups include, but are not limited to, for example, piperidylene, piperazinylene, morpholinylene Azacyclylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene, diazepan, azetidinylene, diazepan, and azabicyclo [3.1.1]Heptanylene and azabicyclo [2.2.1]Heptanylene and azabicyclo [3.2.1]Octane subunit, azabicyclo [2.2.2]Octane subunit, diazabicyclo [3.1.1]Heptanylene and diazabicyclo [2.2.1]Heptanylene and diazabicyclo [3.2.1]Octane subunit, diazabicyclo [2.2.2]Octane subunit, 3-azaspiro [5.5 ]]Undecylenic subunit, 8-azaspiro [4.5 ]]Decane subunit, 2-oxa-8-azaspiro [4.5 ]]Decane subunit, or 3-methyl-2-oxa-8-azaspiro [4.5 ]]Decane subunit. In some embodiments, examples of 6-to 10-membered arylene groups include, but are not limited to, phenylene or naphthylene, for example. In some embodiments, a 5-to 10-membered heteroarylene is a 5-to 10-membered (e.g., 5-to 9-membered, 5-to 8-membered, 5-to 7-membered, or 5-to 6-membered) heteroaryl group containing one nitrogen atom and optionally containing a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, examples of 5-to 10-membered heteroaryl groups include, but are not limited to, for example, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinyl, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazoylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2,1,3 ] ]Oxadiazole subunits and benzo [2,1,3 ]]Thiadiazole subunit, benzo [1,2,3]Thiadiazole subunits, quinolinylene, isoquinolylene, naphthyridine subunits, cinnolinyl, quinazolinylene, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, pyrrolo [2,1-b]Thiazolylene, or imidazo [2,1-b]Thiazole subunits. Each ring W 7 Independently optionally by m 3R a3 Group substitutionEach R is a3 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, or isopropoxy), halogen (e.g. fluoro, chloro, bromo, or iodo), amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 16a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl). m3 represents an integer of 0 to 20, for example, an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 20. The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block.
In some embodiments, each ring W 7 Identical or different and each independently represents:
each ring W 7 Independently optionallyIs m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), C 1-6 Alkoxy (e.g. C 1-5 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, or isopropoxy), halogen (e.g. fluoro, chloro, bromo, or iodo), amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 16a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl). m3 represents an integer of 0 to 20, for example, an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 20. The number of substituents is in principle not subject to any restrictions or is automatically limited by the size of the building block.
In some embodiments, t2 represents an integer of 0.
In some embodiments, t2 represents an integer of 1.
In some embodiments, the W 5 The following groups are represented:
wherein said groups are optionally further substituted with one or more C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), optionally halogenated C 1-6 Alkyl (e.g. optionally halogenated C 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy-, propoxy-, isopropoxy-, butoxy-, sec-butyloxy-or tert-butyloxy), halo-C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-), deuterated C 1-6 Alkoxy (e.g. perdeuterated C 1-4 Alkoxy radicals, e.g. CD 3 -O-、CD 3 CD 2 -O-, or CD 3 CD 2 CD 2 -O-), halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated)Deuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), R 12a -R 11a -or any combination thereof, wherein R 11a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 12a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl); and
the symbol x represents the connection point to LIN.
In some embodiments, R of formula (II) f representation-W 5 -R h -W 5 Wherein R is h Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, symbol represents the point of attachment to LIN, and W 5 As defined herein. In some embodiments, R h Represents optionally substituted C 1-6 Alkylene (e.g. C 1-5 Alkylene, C 1-4 Alkylene or C 1-3 Alkylene, for example methylene, ethylene, propylene, isopropylene, butylene, sec-butylene, tert-butylene, pentylene or hexylene), and the said C 1-6 Alkylene groups optionally being substituted with one or more groups selected from halogen (e.g. fluoro, chloro, bromo or iodo), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 An alkoxy group, or any combination thereof. In some embodiments, R h Represents optionally substituted methylene, which is optionally substituted by one or more groups selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 An alkoxy group, or any combination thereof.
In some embodiments, the R f The following groups are represented:
bond, -O-, -NHC (O) -, -C (O) NH-, -N (CH) 3 )-、-N(CH 3 )-(CH 2 ) 2 -N(CH 3 )-*、-N(CH 3 )-(CH 2 ) 3 -N(CH 3 )-*、-NH-(CH 2 ) 2 -N(CH 3 )-*、-N(CH 3 )-(CH 2 ) 3 -NH-*、-CH 2 -NHC(O)-*、-CH 2 -C(O)NH-*、-CH 2 -NH-*、-O-(CH 2 ) 2 -N(CH 3 )-*、-O-(CH 2 ) 2 -NH-, or-CH 2 -N(CH 3 ) -, or
Wherein said groups are optionally further substituted with one or more C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally halogenated C 1-6 Alkyl (e.g. optionally halogenated C 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、C 1-6 Alkoxy (e.g. C 1-4 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, tert-butyloxy, pentoxy, or hexyloxy), halogen (e.g. fluorine, chlorine, bromine or iodine), amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), R 12a -R 11a -or any combination thereof, wherein R 11a Is optionally substituted C 1-6 Alkylene (e.g. optionally substituted C 1-4 Alkylene, e.g. optionally substituted methylene, ethylene or propylene) or optionally substituted C 2-6 Alkenylene (e.g. optionally substituted C 2-4 Alkenylene, e.g. optionally substituted ethenylene, propenylene, butenylene), R 12a Represents halogen (e.g. fluorine, chlorine, bromine or iodine), R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl (e.g., methyl, ethyl, or propyl); and
the symbol x represents the connection point to LIN.
In some embodiments, the ULM represents the structure of formula (ULM-1), formula (ULM-2), formula (ULM-3), formula (ULM-4), formula (ULM-5), formula (ULM-6), formula (ULM-7), formula (ULM-8), formula (ULM-9), formula (ULM-10), formula (ULM-11), or formula (ULM-12) below.
Wherein the method comprises the steps of
A represents CO or CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halo C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)；
(R b ) n Represents the benzene ring optionally substituted by n R b Substituted, each R b Identical or different and each independently represents hydrogen, deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy-, propoxy-, isopropoxy-, butoxy-, sec-butyloxy-or tert-butyloxy), halo-C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally substituted C 3-6 Cycloalkyl (e.g., optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), or C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups such as ethynyl, propynyl, or butynyl); and
n represents an integer of 0, 1, 2 or 3.
In some embodiments, the ULM represents the structure of formula (ULM-13), formula (ULM-14), formula (ULM-15), formula (ULM-16), formula (ULM-17), formula (ULM-18), formula (ULM-19), formula (ULM-20), formula (ULM-21), formula (ULM-22), formula (ULM-23), or formula (ULM-24) below.
Wherein said A, (R) b ) n 、R b As defined hereinabove.
In some embodiments, the ULM represents a structure of the formula:
in some embodiments, LIN of the compound of formula (II) represents the structure of the formula:
wherein R is 5 And R is 6 Identical or different and each independently represents:
hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight or branched C 2-30 An alkyl group, a hydroxyl group,
wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene group),Alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof; and
Hydrogen of the methyl group and the C 2-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
In some embodiments, R of the compound of formula (II) 5 Represents hydrogen, fluorine, chlorine, bromine, iodine, or optionally substituted methyl. The hydrogen of the methyl group is optionally further replaced by a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, R of the compound of formula (II) 5 Represents optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof; and
the C is 2-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, R of the compound of formula (II) 6 Represents hydrogen, fluorine, chlorine, bromine, iodine, or optionally substituted methyl. The hydrogen of the methyl group is optionally further replaced by a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, R of the compound of formula (II) 6 Represents optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are independently of each other optionallyFurther selected from deuterium, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof; and
the C is 2-30 One or more CH's of alkyl groups 2 Optionally further selected fromSubstitution of substituents: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof.
In some embodiments, R of the compound of formula (II) 5 And R is 6 Representing the same or different and eachIndependently of the representation:
hydrogen, fluorine, chlorine, bromine or iodine, or
-C 1-30 An alkyl group;
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -(R c -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -(R d -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R c -R d -(C(R a6 )(R a7 )) n2 ) m4 -CH 3 ；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -R c -(C(R a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
Wherein each group R c Selected from O, N (R) e )、C(O)、C(O)O、OC(O)、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl); each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluoro, chloro, bromo, or iodo), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
the C is 1-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 An alkoxy group, an amino group,for example methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any combination thereof;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any combination thereof; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
In some embodiments, R of the compound of formula (II) 5 And R is 6 The structures of the following formulae are identical or different and are each independently represented:
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(N(R e )-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(C(O)N(R e )-
(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -C(O)N(R e )-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)N(R e )-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 -C(O)-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 Arylene- (C (R) a8 )(R a9 )) n3 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heterocyclylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heteroarylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 - (cycloalkylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
Wherein each R e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
the cycloalkylene group (e.g. C 3-20 Cycloalkylene), the arylene group (e.g. C 3-20 Arylene), said heterocyclylene (e.g., 4-to 20-membered heterocyclylene) and said heteroarylene (e.g., 4-to 20-membered heteroarylene) independently of each other are optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluoro, chloro, bromo, or iodo), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.gSuch as F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
R a1 、R a2 、R a3 、R a4 、R a5 、R a6 、R a7 and R is a8 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen (e.g., fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxyPropoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-) or any combination thereof; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
In some embodiments, R of the compound of formula (II) 5 And R is 6 The same or different and each independently represents the following group:
H. fluorine, chlorine, bromine, iodine, -CH 3 、-CH 2 -CH 3 、-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -CH 3 、-(CH 2 ) 7 -CH 3 、-(CH 2 ) 8 -CH 3 、-(CH 2 ) 9 -CH 3 、-(CH 2 ) 10 -CH 3 、-(CH 2 ) 11 -CH 3 、-(CH 2 ) 12 -CH 3 、-(CH 2 ) 13 -CH 3 、-(CH 2 ) 14 -CH 3 、-(CH 2 ) 15 -CH 3 、-(CH 2 ) 16 -CH 3 、-(CH 2 ) 17 -CH 3 、-(CH 2 ) 18 -CH 3 、-(CH 2 ) 19 -CH 3 、-(CH 2 ) 20 -CH 3 、-(CH 2 ) 21 -CH 3 、-(CH 2 ) 22 -CH 3 、-(CH 2 ) 25 -CH 3 、-(CH 2 ) 29 -CH 3 ；-CH 2 -O-CH 3 、-CH 2 -O-CH 2 -CH 3 、-CH 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 11 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 12 -CH 3 、-(CH 2 ) 3 -O-CH 3 、-(CH 2 ) 3 -O-CH 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 4 -O-CH 3 、-(CH 2 ) 4 -O-CH 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 5 -O-CH 3 、-(CH 2 ) 5 -O-CH 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -O-CH 3 、-(CH 2 ) 6 -O-CH 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 7 -O-CH 3 、-(CH 2 ) 7 -O-CH 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 8 -O-CH 3 、-(CH 2 ) 8 -O-CH 2 -CH 3 、-(CH 2 ) 8 -O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-CH 3 、-CH(CH 3 )-O-CH 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 9 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 10 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 9 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 10 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 4 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 CH 3 、-(CH 2 ) 1 -N(R e )-CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 11 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 1 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 9 -CH 3 、-CH 2 C(O)NHCH 3 、-(CH 2 ) 2 C(O)NHCH 2 CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 C(O)NH(CH 2 ) 7 -CH 3 、U-(CH 2 ) 9 C(O)NH(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 C(O)NH(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -O-CH 2 -CH 3 、-CH 2 NHC(O)CH 3 、-(CH 2 ) 2 NHC(O)CH 2 CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 9 NHC(O)(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 NHC(O)(CH 2 ) 9 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 4 NHC(O)CH 3 、-CH 2 -piperidinyl-CH 3 、-CH 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperidinyl-CH 3 、-(CH 2 ) 3 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperidinyl-CH 3 、-(CH 2 ) 4 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperidinyl-CH 3 、-(CH 2 ) 5 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperidinyl-CH 3 、-(CH 2 ) 6 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperidinyl-CH 3 、-(CH 2 ) 7 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperidinyl-CH 3 、-(CH 2 ) 8 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-CH 2 -sub-piprazolePyridyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -sub-piprazolePyridyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -sub-piprazolePyridyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -piperazinylene-CH 3 、-CH 2 -piperazinylene-CH 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperazinylene-CH 3 、-(CH 2 ) 2 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperazinylene-CH 3 、-(CH 2 ) 3 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperazinylene-CH 3 、-(CH 2 ) 4 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperazinylene-CH 3 、-(CH 2 ) 5 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperazinylene-CH 3 、-(CH 2 ) 6 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperazinylene-CH 3 、-(CH 2 ) 7 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperazinylene-CH 3 、-(CH 2 ) 8 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 6 -CH 3 Or- (CH) 2 ) 8 -piperazinylene- (CH) 2 ) 7 -CH 3 ；
Wherein said piperidinyl and said piperazinyl independently of each other are optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), hydroxy, amino, mercapto, halogen (e.g., fluoro, chloro, bromo, or iodo), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 -)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-, cyano-, or any combination thereof;
CH in said group 3 Hydrogen and one or more CH 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g. halogenated C) 1-4 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally deuterated C 1-6 Alkoxy (e.g. optionally deuterated C 1-4 Alkoxy groups, e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), optionally deuterated C 1-6 alkyl-NH- (e.g. optionally deuterated C) 1-3 alkyl-NH-, e.g. CH 3 NH-、CH 3 CH 2 NH-or CH 3 CH 2 CH 2 NH-)、NH 2 -C 1-6 Alkylene (e.g. NH 2 -C 1-3 Alkylene-, e.g. NH 2 CH 2 -、NH 2 CH 2 CH 2 -and NH 2 CH 2 CH 2 CH 2 (-), optionally deuterated C 1-6 alkyl-NHC (O) - (e.g. optionally deuterated C 1-4 alkyl-NHC (O) -, e.g. CH 3 -NHC(O)-、CH 3 CH 2 -NHC (O) -, and CH 3 CH 2 CH 2 -NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH- (e.g. optionally deuterated C) 1-4 alkyl-C (O) NH-, e.g. CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C (O) NH-), or any combination thereof;
each R is e Independently represent H or C 1-6 Alkyl (e.g. C 1-4 Alkyl or C 1-3 Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl); and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
In some embodiments, the-R f -LIN-represents the following group:
-CH 2 -、-O-CH 2 -**、-NHC(O)-CH 2 -**、-C(O)NH-CH 2 -**、-NH-CH 2 -**、-N(CH 3 )-CH 2 -**、-N(CH 3 )-(CH 2 ) 2 -N(CH 3 )-CH 2 -**、-N(CH 3 )-(CH 2 ) 3 -N(CH 3 )-CH 2 -**、-NH-(CH 2 ) 2 -N(CH 3 )-CH 2 -**、-N(CH 3 )-(CH 2 ) 3 -NH-CH 2 -**、-CH 2 -NHC(O)-CH 2 -**、-CH 2 -C(O)NH-CH 2 -**、-CH 2 -NH-CH 2 -**、-O-(CH 2 ) 2 -N(CH 3 )-CH 2 -**、-O-(CH 2 ) 2 -NH-CH 2 -, x or-CH 2 -N(CH 3 )-CH 2 -, or
Wherein the groups are optionally further substituted with one or more (e.g. 1-10, 1-8, 1-6, such as 1, 2, 3, 4, 5 or 6) C's selected from deuterium, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, amino, carboxyl, optionally deuterated C' s 1-6 Alkyl (e.g. optionally deuterated C 1-4 Alkyl or optionally deuterated C 1-3 Alkyl radicals, e.g. methyl, CD 3 Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally halogenated C 1-6 Alkyl (e.g. optionally halogenated C 1-4 Alkyl or optionally halogenated C 1-3 Alkyl radicals, e.g. F 3 C-、FCH 2 -、F 2 CH-、ClCH 2 -、Cl 2 CH-、CF 3 CF 2 -、CF 3 CHF-、CHF 2 CF 2 -、CHF 2 CHF-、CF 3 CH 2 -or CH 2 ClCH 2 (-), deuterated C 1-6 Alkyl (e.g. perdeuterated C 1-4 Alkyl or perdeuterated C 1-3 Alkyl groups, e.g. perdeuterated methyl groups (CD) 3 ) Ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, C) 1-6 Alkoxy (e.g. C 1-4 Alkoxy or C 1-3 Alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halo C 1-6 Alkoxy (e.g. halogenated C 1-4 Alkoxy radicals, e.g. F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-), deuterated C 1-6 Alkoxy (e.g. perdeuterated C 1-4 Alkoxy groups, e.g. D 3 C-O-、CD 3 CD 2 -O-, or CD 3 CD 2 CD 2 -O-)、C 2-6 Alkynyl groups (e.g. C 2-4 Alkynyl groups, e.g. ethynyl, propynyl, or butynyl), C 2-6 Alkenyl (e.g. C 2-4 Alkenyl groups, e.g. ethenyl, propenyl, or butenyl), optionally deuterated C 3-6 Cycloalkyl (e.g., optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or any combination thereof; wherein the symbols denote the connection points to the ULM.
Herein, when PBM of the compounds of formula (II) of the present disclosure represents the following structural formula:
and at the same time-R f -LIN-representation
Wherein the symbols denote the points of attachment to the ULM, (R) b ) n The benzene ring of formula (ULM) is substituted with 1, 2 or 3R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl groups.
In some embodiments, the compound of formula (II) is also represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21), formula (II-22), formula (II-23), formula (II-24), formula (II-25), formula (II-26), formula (II-27), formula (II-28), formula (II-29), formula (II-30), formula (II-31), formula (II-32), formula (II-33), formula (II-34), formula (II-35), formula (II-36), formula (II-37), formula (II-39), formula (II-40), formula (II-41), formula (II-42), formula (II-43), formula (II-44), formula (II-45), formula (II-46), formula (II-47), formula (II-48), formula (II-49), formula (II-50), formula (II-51), formula (II-52), formula (II-53), formula (II-55), formula (II-56), formula (II-57), formula (II-58), formula (II-59), formula (II-60), formula (II-61), formula (II-62), formula (II-63), formula (II-64), formula (II-65) or formula (II-66) are represented by the structure:
Therein, A, R 1 、R 2 、R 3 、R 4 、(R b ) n 、LIN、R f 、(R 1 ) p1 、(R 2 ) p2 、(R 4 ) p3 、(R 5 ) p4 、(R 7 ) p5 、R 8 、(R 9 ) p6 、R 10 、(R 11 ) p7 、R 12 、R 13 、R 14 Ring A, ring B, ring C, R 15 、(R 16 ) p9 、X 1 、X 2 、X 3 、(R 20 ) p10 、R 21 、R 22 、(R 23 ) p11 、(R 24 ) p12 、R 25 、X 4 、X 5 、X 6 、X 7 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、(R 34 ) p13 、R 35 、(R 36 ) p14 、R 37 、X 8 、X 9 、X 10 、X 11 、X 12 、R 38 、R 39 、(R 40 ) p15 、(R 42 ) p16 、(R 43 ) p17 、(R 44 ) p18 、(R 45 ) p19 、(R 46 ) p20 、(R 48 ) p21 、(R 49 ) p22 、R 50 、R 51 、(R 52 ) p23 、(R 53 ) p24 、R 54 、R 55 、R 56 、R 57 、(R 58 ) p25 、X 13 、R 59 、R 60 、R 61 、R 62 、R 63 、R 64 、(R 65 ) p26 、R 66 、R 67 、R 68 、R 69 、R 70 、X 14 、X 15 、R 73 、R 74 、R 75 、R 76 、R 77 、R 78 、R 79 、R 80 、R 81 、X 16 、X 17 、R 82 、R 83 、R 84 、R 85 、R 86 、R 87 、R 88 、R 89 、R 90 、(R 91 ) p27 、(R 92 ) p28 、(R 93 ) p29 、R 94 、R 95 、(R 96 ) p30 、(R 97 ) p31 、X 18 、X 19 、X 20 、X 21 、X 22 、R 98 、R 99 、R 100 、R 101 、R 102 、R 103 、X 23 、(R 104 ) p32 、(R 105 ) p33 、(R 106 ) p34 、(R 107 ) p35 、(R 108 ) p36 、(R 109 ) p37 、(R 110 ) p38 、(R 111 ) p39 、R 112 、R 113 、R 114 、R 115 、R 116 、R 117 、R 118 、(R 119 ) p40 、R 120 、R 121 、R 122 、R 123 、(R 125 ) p41 、(R 127 ) p43 、R 131 、R 132 、(R 133 ) p46 、(R 134 ) p47 、(R 135 ) p48 、R 136 、(R 137 ) p49 、X 24 、X 25 、X 26 、R 138 、R 139 、R 140 、(R 141 ) p50 、R 142 、(R 143 ) p51 、(R 144 ) p52 、(R 145 ) p53 、(R 146 ) p54 、R f2 、(R 147 ) p55 、R 148 、(R 149 ) p56 、X 27 Ring I, R 150 、(R 151 ) p57 、(R 152 ) p58 、(R 153 ) p59 、X 28 、X 29 、X 30 、(R 154 ) p60 、R 155 、R 156 、R 157 、R 158 、(R 159 ) p61 、X 31 、(R 160 ) p62 Rings J and (R) 161 ) p63 As defined above for the compounds of formula (II) and their respective sub-embodiments.
In some embodiments, provided are specific compounds of formula (II) of table 3 below and salts (including pharmaceutically acceptable salts, e.g., their hydrochloride salts), prodrugs, solvates, isotopically enriched analogs, polymorphs, stereoisomers (including enantiomers and diastereomers), or mixtures of stereoisomers thereof:
TABLE 3 Compounds of the present disclosure
Other forms of the compounds (including salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs, or polymorphs of the compound)
The compounds of the present disclosure have the formula (I), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21), formula (II-22), formula (II-23), formula (II-24), formula (II-25), formula (II-26), formula (II-27), formula (II-28), formula (II-29), formula (II-30), formula (II-31), formula (II-32), formula (II-33), formula (II-34), formula (II-35), formula (II-36), formula (II-38), A structure of any of formula (II-39), formula (II-40), formula (II-41), formula (II-42), formula (II-43), formula (II-44), formula (II-45), formula (II-46), formula (II-47), formula (II-48), formula (II-49), formula (II-50), formula (II-51), formula (II-52), formula (II-53), formula (II-54), formula (II-55), formula (II-56), formula (II-57), formula (II-58), formula (II-59), formula (II-60), formula (II-61), formula (II-62), formula (II-63), formula (II-64), formula (II-65) or formula (II-66). Unless otherwise indicated, when referring to compounds of the present disclosure, reference is made to compounds comprising formula (I), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21), formula (II-22), formula (II-23), formula (II-24), formula (II-25), formula (II-26), formula (II-27), formula (II-28), formula (II-29), formula (II-30), formula (II-31), formula (II-32), formula (II-33), formula (II-34), formula (II-35), formula (II-36) and formula (II-37), formula (II-38), formula (II-39), formula (II-40), formula (II-41), formula (II-42), formula (II-43), formula (II-44), formula (II-45), formula (II-46), formula (II-47), formula (II-48), formula (II-49), formula (II-50), formula (II-51), formula (II-52), formula (II-53), formula (II-54), formula (II-55), formula (II-56), formula (II-57), formula (II-58), formula (II-59), formula (II-60), formula (II-61), formula (II-62), formula (II-63), formula (II-64), formula (II-65) or formula (II-66), and specific compounds falling within the scope of these formulae.
It is to be appreciated that the compounds of the present disclosure (including formula (I), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21), formula (II-22), formula (II-23), formula (II-24), formula (II-25), formula (II-26), formula (II-27), formula (II-28), formula (II-29), formula (II-30), formula (II-31), formula (II-32), formula (II-33), formula (II-34), formula (II-35), formula (II-36), formula (II-37), the compounds of formula (II-38), formula (II-39), formula (II-40), formula (II-41), formula (II-42), formula (II-43), formula (II-44), formula (II-45), formula (II-46), formula (II-47), formula (II-48), formula (II-49), formula (II-50), formula (II-51), formula (II-52), formula (II-53), formula (II-54), formula (II-55), formula (II-56), formula (II-57), formula (II-58), formula (II-59), formula (II-60), formula (II-61), formula (II-62), formula (II-63), formula (II-64), formula (II-65) or formula (II-66) may have a steric configuration and thus may exist in more than one stereoisomer. The disclosure also relates to optically enriched compounds having a steric configuration, such as greater than 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures. As used herein, "optically enriched" means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer, and can be described by enantiomeric excess (ee%). Purification of the isomers and separation of the isomer mixtures may be accomplished by standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates), chiral resolution, and/or the like).
In some embodiments, polymorphic forms of the compounds of the present disclosure or salts of the compounds of the present disclosure are also provided. Salts of the compounds of the present disclosure may be pharmaceutically acceptable salts including, but not limited to, halogen acidsSalts (including hydrochloride, hydrobromide), sulfate, citrate, maleate, mesylate, citrate, lactate, L-tartrate, fumarate, L-malate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate, p-toluenesulfonate, and the like. The compounds of the present disclosure can exist in a pharmaceutically acceptable solvent such as water, ethanol, and the like, in the form of non-solvates or solvates. In some embodiments, compounds of the present disclosure may be prepared as prodrugs or prodrugs. The prodrug can be converted into the parent drug in the body to act. In some embodiments, isotopically-labeled compounds of the present disclosure are also provided, examples of isotopes including deuterium (D or 2 H)。
III pharmaceutical composition/formulation
In some embodiments, the present disclosure provides a pharmaceutical composition comprising as an active ingredient a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, and at least one pharmaceutically acceptable carrier.
In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in this disclosure, and not deleterious to the patient, and must be "acceptable". Some examples of materials for pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; polyoxyethylene, polyvinylpyrrolidone, polyacrylamide, poloxamer; and other non-toxic compatible substances used in pharmaceutical formulations.
The pharmaceutical compositions described in the present disclosure further comprise at least one second therapeutic agent, such as an anticancer agent. The second therapeutic agent may be used in combination with a compound of formula (I) or formula (II) as described in the present disclosure to treat a disease or disorder as described in the present disclosure. The second therapeutic agent includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, a gene therapeutic agent, and the like.
The pharmaceutical compositions described herein comprising as an active ingredient a compound of formula (I) or formula (II) as described herein, or a pharmaceutically acceptable salt thereof, may be prepared in the form of suitable formulations, such as spray formulations, patches, tablets (e.g. conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (e.g. soft, hard capsules, enteric capsules), dragees, lozenges, powders, granules, powder injection, suppositories, or liquid formulations (e.g. suspensions (e.g. aqueous or oily suspensions), solutions, emulsions or syrups), or conventional injectable solutions (e.g. injectable solutions using water, ringer's solution or isotonic sodium chloride solution as a sterile solvent or injectable solution according to known methods in the art), according to suitable routes of administration, including, but not limited to, nasal administration, inhalation, topical administration, oral mucosal administration, rectal administration, pleural cavity administration, intraperitoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration. The person skilled in the art can also prepare the compounds of formula (I) or (II) as desired in conventional, dispersible, chewable, orally rapidly disintegrating or fast dissolving formulations, or in slow-release or controlled-release capsules.
The compounds of formula (I) as described in the present disclosure as active ingredients are contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount for the indication in need of treatment without causing serious toxic effects in the treated subject. The dosage of active compound for use in all diseases or conditions mentioned herein is, for example, from about 5ng/kg subject body weight/day to 500mg/kg subject body weight/day, from about 10ng/kg subject body weight/day to 300mg/kg subject body weight/day, for example, from 0.1 to 100mg/kg subject body weight/day, or from 0.5 to about 25mg/kg subject body weight/day.
The compounds of formula (I) or pharmaceutically acceptable salts thereof described in this disclosure may be conveniently administered in any suitable formulation format, including, but not limited to, containing less than 1mg,1mg to 3000mg,5mg to 1000mg, e.g., 5 to 500mg,25 to 250mg of active ingredient per unit dosage form.
The compound of formula (II) as described in the present disclosure as an active ingredient is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to a subject for an indication in need of treatment without causing serious toxic effects in the treated subject. The dosage of active compound for use in all diseases or conditions mentioned herein is, for example, from about 5ng/kg subject body weight/day to 500mg/kg subject body weight/day, from about 10ng/kg subject body weight/day to 300mg/kg subject body weight/day, for example, from 0.1 to 100mg/kg subject body weight/day, or from 0.5 to about 25mg/kg subject body weight/day.
The compound of formula (II) or a pharmaceutically acceptable salt thereof described in the present disclosure may be conveniently administered in any suitable formulation format, including, but not limited to, containing less than 1mg,1mg to 3000mg,5mg to 1000mg, e.g., 5 to 500mg,25 to 250mg of active ingredient per unit dosage form.
IV kit/packaging article
A compound of formula (I) or formula (II), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, as described in the present disclosure, for use as a medicament. The pharmaceutical agents of the present disclosure or the pharmaceutical compositions of the present disclosure may be present in a kit/packaging article. The kit/packaging article may comprise a package or container. Packaging or containers include, but are not limited to, ampoules (ampoules), blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packages, co-extruded film infusion containers, test tubes, dispensing devices, and the like. The kit/packaging article may contain instructions for use of the product.
V, method and use
The compounds of formula (I), or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, described herein, may also be used as medicaments. In particular, the compounds of formula (I) described herein, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, may be used in the manufacture of a medicament for use in the prevention and/or treatment of a disease or condition mediated by the cereblon protein.
A method for preventing and/or treating a cereblon protein-mediated disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein as an active ingredient. In some embodiments, the cereblon protein-mediated disease or disorder comprises: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, weng Weili Hiruder syndrome, richter Syndrome (RS), acute liver failure or diabetes. In some embodiments, the cereblon protein-mediated disease or disorder includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas, including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer; inflammatory myofibroblastic tumor; colorectal cancer; glioma of brain; astrocytoma; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; weng Weili Hirudt syndrome; richter Syndrome (RS); sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; autoinflammatory diseases including gout and the like; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; congestive heart failure; myocardial infarction; multiple organ failure due to cachexia and septic shock; or acute liver failure.
In a method for preventing and/or treating a cereblon-mediated disease or condition in a subject, a therapeutically effective amount of a compound of formula (I) as described in the present disclosure, or a pharmaceutical composition comprising a compound of formula (I) as described in the present disclosure as an active ingredient, is administered to the subject by at least one administration mode selected from nasal administration, inhalation administration, topical administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural cavity administration, intrathecal administration and intravenous administration.
A compound of formula (II), or a pharmaceutically acceptable salt, solvate, isotopically enriched analog, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, as described herein, may be used as a medicament. In particular, the compounds of formula (II), or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, described herein, may be used in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, weng Weili Hirschner syndrome, richter Syndrome (RS), acute liver failure, diabetes, kennedy disease, seborrheic alopecia, hirsutism, skin diseases, cardiovascular diseases, dysfunctional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, transplant rejection, polycystic ovary syndrome, or thyroid diseases. In some embodiments, the disease or disorder includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas, including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma of brain; astrocytoma; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; weng Weili Hirudt syndrome; richter Syndrome (RS), sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; autoinflammatory diseases including gout and the like; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; multiple organ failure due to cachexia and septic shock; acute liver failure; functional uterine bleeding; anemia; aplastic anemia of children; endometriosis; polycystic ovary syndrome; thyroid diseases; cardiovascular disease (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); skin diseases (e.g., acne); kennedy disease (Kennedy disease); seborrheic alopecia; and hirsutism.
Methods for preventing and/or treating a disease or disorder in a subject include administering to the subject a therapeutically effective amount of a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein that includes a compound of formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the disease or disorder includes, but is not limited to, a tumor, an infectious disease, an autoinflammatory disease, an inflammatory disease, an autoimmune disease, a neurological disease, a respiratory disease, anemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, weng Weili-Hirschter syndrome (Richter syndrome, RS), acute liver failure, diabetes, nickendi disease (Kennedy disease), seborrheic alopecia, hirsutism, skin diseases, cardiovascular diseases, functional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, transplant rejection, thyroid syndrome, and multiple-bladder disease. In some embodiments, the disease or disorder includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas, including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma and lung squamous carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; glioma of brain; astrocytoma; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; weng Weili Hirudt syndrome; richter Syndrome (RS); sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; autoinflammatory diseases including gout and the like; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; multiple organ failure due to cachexia and septic shock; acute liver failure; functional uterine bleeding; anemia; aplastic anemia of children; endometriosis; polycystic ovary syndrome; thyroid diseases; cardiovascular disease (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); skin diseases (e.g., acne); kennedy disease (Kennedy disease); seborrheic alopecia; and hirsutism.
The term "treatment" or "treatment" refers to the administration of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, as described in the present disclosure, or a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, as an active ingredient, to a subject to slow (alleviate) the progression of an undesired disease or disorder (e.g., tumor). Beneficial or desired clinical results of the present disclosure include, but are not limited to: alleviating symptoms, lessening the severity of the disease, stabilizing the state of the disease, delaying or slowing the progression of the disease, improving or alleviating the condition, and alleviating the disease.
The "therapeutically effective amount" of a compound of the present disclosure depends on a variety of factors including the activity of the particular compound being used, the metabolic stability and length of action of that compound, the age, sex, and weight of the patient, the general medical condition of the patient, the mode and time of administration, the rate of excretion, drug combination, and the disease or condition of the patient being treated. One skilled in the art will be able to determine the appropriate dosage based on these and other factors.
It will be appreciated that the choice of the active compound(s) and/or composition(s) and the dosage thereof will depend on the individual base case (the individual case should generally be optimized). The administration and dosing regimen should be within the ability of those skilled in the art, and the appropriate dosage will depend on many factors including the level of knowledge of the ordinarily skilled physician, veterinarian or researcher (see, e.g., lijun monograph, "clinical pharmacology", 4 th edition, human health Press (2008)).
The patient or subject treated as described above refers to an animal, such as a mammal, including but not limited to a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mouse, etc.
The compounds of formula (I) described herein, or pharmaceutically acceptable salts, solvates, isotopically enriched analogs, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, may be used to prepare compounds of formula (II) of the present disclosure. The compounds of formula (II) of the present disclosure can be used for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, weng Weili Hirschner syndrome, richter Syndrome (RS), acute liver failure, diabetes, kennedy disease, seborrheic alopecia, hirsutism, skin diseases, cardiovascular diseases, dysfunctional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis, transplant rejection, polycystic ovary syndrome, or thyroid diseases.
VI definition of
The following words, phrases and symbols used in the present specification have the meanings as described below in general unless otherwise indicated.
Generally, the nomenclature used herein (including IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, pharmacology, and the like) are those well known and commonly employed in the art. Unless defined otherwise, all scientific and technical terms used herein in connection with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, in the claims and/or the specification, the terms "a" or "an" when used in conjunction with the term "comprising" or noun may have the meaning of "one" but are also consistent with the meaning of "one or more", "at least one", and "one or more". Similarly, the term "another" or "other" may mean at least a second or more.
It will be understood that whenever aspects are described herein by the terms "comprising" or "including," other similar aspects are provided as described by "consisting of …" and/or "consisting essentially of ….
The term "about" alone or in combination is used herein to mean approximately, about, or around …. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" can modify a value above and below the stated value by changing, for example, 10%, 5%, 2%, or 1% up or down (up or down).
The term "… …, used herein, alone or in combination, means a bond" meaning that it is a bond connector (i.eIndicating that it is not present). For example, the term "R f The meaning of the bond "means R f Is a bond linkage. In other words, when R f In the case of bonds, the radical PBM of the structure of the formula (II) is directly linked to LIN in the structure of the formula (I). For example, the term "R 17 The meaning of the bond "means R 17 Is a bond linkage. In other words, when R 17 In the case of a bond, the ring atom C of the structure of formula (PBM-9) is directly attached to R in the compound of formula (II) f 。
The term "optionally substituted" as used herein, alone or in combination, means that the indicated group may be unsubstituted or substituted with one or more substituents as defined herein. The term "optionally substituted with … …" is used interchangeably herein with "unsubstituted or substituted. The term "substituted" generally means that one or more hydrogens in the structure referred to are replaced with a specific substituent, either the same or different. The number of substituents is in principle not subject to any restrictions, or is automatically limited by the size of the building unit (i.e. the total number of hydrogen atoms that can be replaced of the building unit), or is as defined explicitly herein.
As used herein, the term "straight or branched C", alone or in combination 2-30 The main carbon chain of the alkylene group having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d The "insertions" in any combination "of (a) have the definitions known in the art, i.e. can refer to the radicals R c 、R d Or a group R c And R is R d And breaking carbon-carbon bonds between one or more pairs of adjacent carbon atoms of the main carbon chain. Herein, examples of the above term "inserted with one or more" may include, but are not limited to, the insertion of one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R as defined herein into the main carbon chain c And/or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R d And/or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R c And R is R d The backbone groups thus formed conform to covalent bond theory. For example, the expression "straight-chain or branched C 2-30 The main carbon chain of the alkylene group having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of (C) means straight or branched chain C 2-30 One or more pairs of any two adjacent carbon atoms in the main carbon chain of the alkylene chain are interrupted by one or more (e.g. 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) R c And/or R d And/or one or more radicals R c And R is R d To form a composition containing one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) "-CH 2 -R c -CH 2 "fragments and/or one or more (e.g.1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1)" -CH 2 -R d -CH 2 "fragments and/or one or more (e.g.1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1)" -CH 2 -R c -R d -CH 2 - "fragments, wherein each R c Identical or different, each R d The same or different, and as defined herein.
In the context of the present disclosure, it is to be understood that the expression "the straight or branched chain C 2-30 The main carbon chain of the alkylene group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d "including" the straight or branched chain C 2-30 The main carbon chain of the alkylene group having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of "and" the straight or branched chain C 2-30 The main carbon chain of the alkylene radical not being interrupted by one or more radicals R c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of the above).
In this context, the bond broken by the wavy line shows the point of attachment of the depicted group to the rest of the molecule. For example, a group represented by the formula (ULM) shown below
The benzene ring representing said group is linked to the group LIN of the compound of formula (II). For example, the group represented by LIN depicted below:
methylene groups representing said groups are respectively associated with R f And ULM connection.
The term "the C" used herein, alone or in combination x-y One or more CH's of alkylene groups 2 The replacement of hydrogen of (a) by … "means a straight or branched chain C x-y Any one or more CH in alkylene 2 Is replaced by a substituent as defined herein. Herein, "group-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 -、-(CH 2 ) 8 -、-(CH 2 ) 9 -、-(CH 2 ) 10 -、-(CH 2 ) 11 -、-(CH 2 ) 12 -、-(CH 2 ) 13 -、-(CH 2 ) 14 -、-(CH 2 ) 15 -、-(CH 2 ) 16 -、-(CH 2 ) 17 -、-(CH 2 ) 18 -、-(CH 2 ) 19 -、-(CH 2 ) 20 -、-(CH 2 ) 21 -、-(CH 2 ) 22 -、-(CH 2 ) 25 -, a part of or- (CH) 2 ) 30 -one or more CH 2 The term "one or more" in the "hydrogen of each alkylene group" may refer to part or all of the hydrogen mentioned, including but not limited to 1 to 60 hydrogens. In some embodiments, the term "one or more CH 2 Hydrogen of (2)"may refer to some or all of the hydrogens of the alkylene groups mentioned, including but not limited to 1-30, such as 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, or 1 hydrogen. In some embodiments, the term "one or more CH 2 The hydrogen of (2) may refer to 1 to 3 of the plurality of hydrogens of the alkylene group mentioned. The number is in principle not limited by any restrictions or by the size of the building elements.
In this context, the term "oxo" or "oxo" refers to = O.
As used herein, the term "nicotinyl" refers to
The term "halogen atom" or "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" as used herein, alone or in combination, refers to a straight or branched chain alkyl group. The term "C x -C y Alkyl "or" C x-y Alkyl "(x and y are each integers) refers to a straight or branched chain alkyl group containing from x to y carbon atoms. The term "C" used in the present invention alone or in combination 1-10 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms. C of the present disclosure 1-10 Examples of alkyl groups include C 1-9 Alkyl, C 1-8 Alkyl, C 2-8 Alkyl, C 1-7 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, and C 1-3 An alkyl group. Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl and decyl. The term "C" of the present disclosure 1-3 Alkyl "or" C 1 -C 3 Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms, representative examples of which include methyl, ethyl, n-propyl, and isopropyl. In the present disclosure, the "alkyl" is optionally substituted, the substituents being optionally one or more groups selected from halogen, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Substituents for alkoxy, trifluoromethyl, heterocyclyl, or combinations thereof.
The term "haloalkyl" as used herein, alone or in combination, refers to a straight or branched chain alkyl group substituted with one or more halogens wherein one or more hydrogens in the alkyl group are replaced with a halogen. The term "halogenated C x -C y Alkyl "or" halo C x-y Alkyl "(x and y are each integers) refers to a straight or branched chain alkyl group containing from x to y carbon atoms substituted with one or more halogens. The term "haloC" used in this disclosure, alone or in combination 1-10 Alkyl "refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms substituted with one or more halogens. Halogenated C of the present disclosure 1-10 Examples of alkyl groups include halogenated C 1-9 Alkyl radicals, e.g. halogenated C 1-8 Alkyl, halo C 2-8 Alkyl, halo C 1-7 Alkyl, halo C 1-6 Alkyl, halo C 1-5 Alkyl, or halo C 1-4 An alkyl group. Representative examples include halomethyl, haloethyl, halon-propyl, haloisopropyl, halon-butyl, haloisobutyl, halosec-butyl, halotert-butyl, halopentyl, haloisopentyl, haloneopentyl, haloterpentyl, halohexyl, haloheptyl, halooctyl, halononyl, and halodecyl. The term "halo C" of the present disclosure 1-3 Alkyl "or" halo C 1 -C 3 Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms substituted with one or more halogens, and representative examples thereof include halomethyl, haloethyl, halo-n-propyl, and halo-isopropyl.
The term "deuterated alkyl" as used herein, alone or in combination, refers to a straight or branched chain alkyl group substituted with one or more deuterium atoms wherein one or more hydrogens in the alkyl group are replaced with a deuterium atom. The term "deuterated C x -C y Alkyl "or" deuterated C x-y Alkyl "(x and y are each integers) refers to a straight or branched chain alkyl group containing from x to y carbon atoms substituted with one or more deuterium atoms. The term "deuterated C" used in this disclosure, alone or in combination 1-10 Alkyl "means substituted with one or more deuterium atoms containing 1 to 10 carbon atomsLinear or branched alkyl groups of the molecule. Deuterated C of the present disclosure 1-10 Examples of alkyl groups include deuterated C 1-9 Alkyl radicals, e.g. deuterated C 1-8 Alkyl, deuterated C 2-8 Alkyl, deuterated C 1-7 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-5 Alkyl, or deuterated C 1-4 An alkyl group. Representative examples include perdeuterated methyl (CD) 3 ) Perdeuterated ethyl (CD) 3 CD 2 ) The present invention relates to a process for the preparation of a polymer comprising the steps of (a) perdeuterated n-propyl group, perdeuterated isopropyl group, perdeuterated n-butyl group, perdeuterated isobutyl group, perdeuterated sec-butyl group, perdeuterated tert-butyl group, perdeuterated pentyl group, perdeuterated isopentyl group, perdeuterated neopentyl group, perdeuterated tert-pentyl group, perdeuterated hexyl group, perdeuterated heptyl group, perdeuterated octyl group, perdeuterated nonyl group and perdeuterated decyl group. The term "deuterated C" of the present disclosure 1-3 Alkyl "or" deuterated C 1 -C 3 Alkyl "refers to an alkyl group containing 1 to 3 carbon atoms substituted with one or more deuterium atoms, representative examples of which include perdeuterated methyl (CD) 3 (-) and perdeuterated ethyl (CD) 3 CD 2 )。
The term "alkylene" (which is used interchangeably with "alkylene chain") as used herein, alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen. The term "C x -C y Alkylene "or" C x-y Alkylene "(x and y are each integers) refers to a straight or branched chain alkylene group containing from x to y carbon atoms. C of the present disclosure 1 -C 30 Examples of alkylene groups include C 1 -C 30 Alkylene, C 1 -C 29 Alkylene, C 1 -C 28 Alkylene, C 1 -C 27 Alkylene, C 1 -C 26 Alkylene, C 1 -C 25 Alkylene, C 1 -C 24 Alkylene, C 1 -C 23 Alkylene, C 1 -C 22 Alkylene, C 1 -C 21 Alkylene, C 1 -C 20 Alkylene, C 1 -C 19 Alkylene, C 1 -C 18 Alkylene, C 1 -C 17 Alkylene, C 1 -C 16 Alkylene, C 1 -C 15 Alkylene, C 1 -C 14 Alkylene, C 1 -C 13 Alkylene, C 1 -C 12 Alkylene, C 1 -C 11 Alkylene, C 1 -C 10 Alkylene, C 1 -C 9 Alkylene, C 1 -C 8 Alkylene, C 1 -C 7 Alkylene, C 1 -C 6 Alkylene, C 1 -C 5 Alkylene, C 1 -C 4 Alkylene, C 1 -C 3 Alkylene, or C 1 -C 2 An alkylene group. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, terpentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosanylene, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene. In the present disclosure, the "alkylene" is optionally substituted, the substituents being optionally one or more groups selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 Substituents that are alkyl-C (O) NH-, cyano-, or any combination thereof.
The term "alkoxy", as used herein, alone or in combination, refers to a straight or branched chain alkoxy group having the structural formula alkyl-O-. Alternatively, the alkyl portion of the alkoxy group may contain 1 to 10 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxyA radical, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like. The term "C 1 -C 3 Alkoxy "or" C 1-3 Alkoxy "refers to straight or branched chain alkoxy groups containing 1 to 3 carbon atoms. C (C) 1-3 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.
The term "haloalkoxy" as used herein, alone or in combination, refers to an alkoxy group substituted with one or more halogens. Alternatively, the alkyl portion of the alkoxy group may contain 1 to 10 carbon atoms. Examples of "haloalkoxy" include haloC 1-6 Alkoxy or halo C 1-4 An alkoxy group. Representative examples include, but are not limited to, F 3 C-O-、FCH 2 -O-、F 2 CH-O-、ClCH 2 -O-、Cl 2 CH-O-、CF 3 CF 2 -O-、CF 3 CHF-O-、CHF 2 CF 2 -O-、CHF 2 CHF-O-、CF 3 CH 2 -O-or CH 2 ClCH 2 -O-。
The term "alkylamino", as used herein, alone or in combination, refers to a straight or branched chain alkylamino group having the structural formula alkyl-NH-. Alternatively, the alkyl portion of the alkylamino group may contain 1 to 10 carbon atoms. Representative examples of "alkylamino" include, but are not limited to, methyl-NH-, ethyl-NH-, propyl-NH-, isopropyl-NH-, n-butyl-NH-, isobutyl-NH-, t-butyl-NH-, pentyl-NH-, hexyl-NH-, and the like. The term "C 1 -C 3 alkyl-NH- "or" C 1-3 alkyl-NH- "means a straight or branched chain alkyl-NH-containing from 1 to 3 carbon atoms. C (C) 1-3 Representative examples of alkyl-NH-include, but are not limited to, methyl-NH-, ethyl-NH-, n-propyl-NH-, and isopropyl-NH-.
The term "amino-substituted alkylene" as used herein, alone or in combination, refers to an amino-substituted straight or branched chain alkylene group of the formula NH 2 -alkylene-. Alternatively, the alkylene portion of an "amino substituted alkylene" may contain 1 to 10 carbon atoms. The term "amino-substituted C 1-3 Alkylene "or" amino-C 1-3 Alkyl- "means amino-substituted containingA straight or branched chain alkylene of 1 to 3 carbon atoms. Amino-substituted C 1-3 Representative examples of alkylene groups include, but are not limited to, NH 2 -CH 2 -、NH 2 -CH 2 CH 2 -, a part of NH and NH 2 -CH 2 CH 2 CH 2 -。
The term "alkyl-NHC (O) -" as used herein, alone or in combination, refers to a straight or branched chain alkyl-NHC (O) -, having the structural formula alkyl-NHC (O) -. Alternatively, the alkyl moiety of the alkyl-NHC (O) -can contain 1-10 carbon atoms. The term "C 1 -C 3 alkyl-NHC (O) - "or" C 1-3 alkyl-NHC (O) - "refers to a straight or branched chain alkyl-NHC (O) -, containing from 1 to 3 carbon atoms. C (C) 1-3 Representative examples of alkyl-NHC (O) -include, but are not limited to CH 3 -NHC(O)-、CH 3 CH 2 NHC (O) -, CH 3 CH 2 CH 2 -NHC(O)-。
As used herein, the term "alkyl-C (O) NH-" alone or in combination refers to a straight or branched chain alkyl-C (O) NH-, having the structural formula alkyl-C (O) NH-. Alternatively, the alkyl portion of the alkyl-C (O) NH-may contain 1 to 10 carbon atoms. The term "C 1 -C 3 alkyl-C (O) NH- "or" C 1-3 alkyl-C (O) NH- "means a straight or branched chain alkyl-C (O) NH-containing from 1 to 3 carbon atoms. C (C) 1-3 Representative examples of alkyl-C (O) NH-include, but are not limited to CH 3 -C(O)NH-、CH 3 CH 2 -C (O) NH-, and CH 3 CH 2 CH 2 -C(O)NH-。
In the present invention, the term "heteroaryl", alone or in combination, refers to a 5-to 20-membered (optionally 5-to 15-, 5-to 12-, 5-to 11-, 5-to 10-, 5-to 9-, 5-to 8-, 5-to 7-, 5-to 6-, 6-to 15-, or 6-to 9-membered) monocyclic or bicyclic or polycyclic group containing at least one aromatic ring having 1 or more (e.g., 1-6, or 1-to 4, or 1-to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic or tetracyclic heteroaryl groups in which one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated A partially unsaturated or aromatic ring and may be carbocyclic or contain one or more heteroatoms independently selected from O, S and N. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazole, benzo [2,1,3 ]]Oxadiazolyl and benzo [2,1,3 ]]Thiadiazolyl and benzo [1,2,3 ]]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridinyl, furopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo [1,5-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-a ]]Pyridyl, 1H-pyrrolo [3,2-b ]Pyridyl, 1H-pyrrolo [2,3-b]Pyridinyl, pyrrolo [2,1-b]Thiazolyl and imidazo [2,1-b]Thiazolyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, and xanthenyl. The heteroaryl group may be unsubstituted or substituted. Substituted heteroaryl refers to heteroaryl substituted one or more times (e.g., 1-4, 1-3, or 1-2) with a substituent, wherein the substituent is optionally selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
In the present invention, the term "heteroarylene", alone or in combination, refers to a 5-to 5-membered ring containing at least one aromatic ring having 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfurA 20-membered (optionally 5 to 15, 5 to 12, 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 15 or 6 to 9) mono-, or bi-, or polycyclic divalent group. Bicyclic or polycyclic heteroarylene includes bicyclic, tricyclic, or tetracyclic heteroarylene, wherein one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated, or aromatic and may be carbocyclic or contain one or more heteroatoms independently selected from O, S and N. Examples of monocyclic heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridinyl, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene. Examples of bicyclic heteroarylenes include, but are not limited to, indolylene, isoindolylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienyl, indazolyl, benzimidazolylene, benzoxazolyl, benzisoxazolyl, benzothiazolylene, benzisothiazolylene, benzotriazole, benzo [2,1,3 ] ]Oxadiazolyl and benzo [2,1,3 ] phenylene]Thiadiazolyl, benzo [1,2,3 ] phenylene]Thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridinyl, furanopyridinyl, pteridinyl, purinyl, pyridopyridinyl, pyrazolo [1,5-a ]]Pyridine subunit, pyrazolo [1,5-a ]]Pyrimidine subunit, imidazo [1,2-a]Pyridine subunit, 1H-pyrrolo [3,2-b]Pyridine subunit, 1H-pyrrolo [2,3-b]Pyridine subunit, pyrrolo [2,1-b]Thiazolylene and imidazo [2,1-b]Thiazole subunits. Examples of tricyclic heteroarylene groups include, but are not limited to, acriylene, benzindolyene, carbazolylene, dibenzofuranylene, and xanthylene. The heteroarylene group may be unsubstituted or substituted. Substituted heteroarylene means heteroarylene substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent optionally selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl group,Hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
The term "aryl" as used herein, alone or in combination, refers to a monovalent aromatic hydrocarbon radical containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenyl or naphthyl or fluorenyl. In the present disclosure, the "aryl" is an optionally substituted aryl. Substituted aryl means aryl substituted one or more times (e.g. 1-4, 1-3 or 1-2) with substituents, such as aryl monosubstituted, disubstituted or trisubstituted with substituents, where the substituents are optionally selected, for example, from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
In the present disclosure, the term "arylene" used alone or in combination refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenylene or naphthylene or fluorenylene. In the present disclosure, the "arylene" is an optionally substituted arylene. Substituted arylene means arylene substituted one or more times (e.g., 1-4, 1-3, or 1-2) with a substituent, e.g., arylene monosubstituted, disubstituted, or trisubstituted with a substituent, wherein the substituent is optionally selected from, for example, C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
At the bookThe term "cycloalkyl" as used herein, alone or in combination, refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not being fully conjugated) monocyclic or bicyclic or polycyclic cycloalkyl group, which in some embodiments has 3 to 20 carbon atoms (i.e., C 3-20 Cycloalkyl), or 3 to 15 carbon atoms (i.e., C 3-15 Cycloalkyl) 3 to 12 carbon atoms (i.e. C 3-12 Cycloalkyl), or 3 to 11 carbon atoms (i.e., C 3-11 Cycloalkyl), or 3 to 10 carbon atoms (i.e., C 3-10 Cycloalkyl), or 3 to 8 carbon atoms (i.e., C 3-8 Cycloalkyl), or 3 to 7 carbon atoms (i.e., C 3-7 Cycloalkyl), or 3 to 6 carbon atoms (i.e., C 3-6 Cycloalkyl). The term "cycloalkyl" includes monocyclic, bicyclic or tricyclic cycloalkyl groups having 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic and tricyclic cycloalkyl groups include bridged cycloalkyl, fused and spirocycloalkyl groups such as, but not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl, adamantyl, noradamantyl, bornyl, norbornyl (IUPAC system designation bicyclo [ 2.2.1) ]Heptyl). Herein, the "cycloalkyl" is optionally mono-or poly-substituted, such as, but not limited to, 2-,2,3-,2,4-,2,5-, or 2, 6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkyl" are optionally one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 Substituents that are alkyl-C (O) NH-, cyano-, or any combination thereof. The term "C 3-6 Examples of cycloalkyl "include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.
In the present invention, the term "cycloalkylene", alone or in combination, means a compoundSaturated and partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) mono-or bi-or polycyclic cyclic hydrocarbon divalent radicals having 3 to 12 carbon atoms (e.g., 3-12, 3-11, 3-10, 3-8, 3-7, 3-6 carbon atoms). The term "cycloalkylene" includes monocyclic, bicyclic or tricyclic hydrocarbon divalent radicals having 3 to 12 carbon atoms. Representative examples of monocyclic cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Bicyclic and tricyclic cycloalkylene groups include bridged cycloalkyl, fused ring, and spirocycloalkyl groups such as, but not limited to, decahydronaphthyl, octahydropentalene, octahydro-1H-indenylene, 2, 3-dihydro-1H-indenylene, spirocyclic subunit, adamantylene, noradamantylene, norbornylene (systematic name bicyclo [ 2.2.1) ]Heptane subunits). In the present disclosure, the "cycloalkylene" is optionally mono-or poly-substituted, such as, but not limited to, 2-,2,3-,2,4-,2,5-, or 2, 6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkylene" are optionally one or more substituents selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 Substituents that are alkyl-C (O) NH-, cyano-, or any combination thereof.
The term "C" used herein, alone or in combination x-y Spirocyclic alkylene "or" C x-y The spiroylene group (x and y are each integers) means a spiroylene group having x to y carbon atoms. The term "C" used in the present invention alone or in combination 7-11 Spirocycloalkyl "refers to a spirocycloalkyl group containing 7 to 11 (e.g., 7-10, 7-9) carbon atoms. The term "C 7-11 Representative examples of spirocycloalkyl groups include, but are not limited to, spiro [3.3 ]]Heptanylene, spiro [2.5 ]]Octane subunit, spiro [3.5 ]]Nonane subunit, spiro [4.4]Nonane subunit, spiro [4.5]Decane subunit or spiro [5.5 ]]Undecylenic subunit. The "C 7-11 The spirocycloalkyl group is optionally further substituted with one or more substituents selected from C 1 -C 3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, halo C 1 -C 3 Alkyl, amino substituted C 1-3 Alkylene, C 1-3 alkyl-NHC (O) -, C 1-3 alkyl-C (O) NH-, cyano-, or any combination thereof.
The term "heterocyclyl" or "heterocycloalkyl" as used herein, alone or in combination, refers to a 3 to 20 membered monocyclic, bicyclic, or tricyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, "heterocyclyl" may refer to a 3-to 15-membered (alternatively 3-to 14-membered, 3-to 12-membered, 3-to 11-membered, 3-to 10-membered, 3-to 9-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, 3-to 5-membered, or 4-to 9-membered) saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cycloalkyl group containing one or more heteroatoms (e.g., containing 1-5 or 1-4, 1-3, 1-2 or 1) independently selected from sulfur, oxygen, and nitrogen. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azacyclooctyl, diazepanyl (e.g., 1, 4-diazepan-1-yl), and diazepanyl. Bicyclic and tricyclic heterocyclyl groups include bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl groups, such as, but not limited to, representative examples include, but are not limited to, 6-azabicyclo [3.1.1 ]Heptan-3-yl, 2, 5-diazabicyclo [2.2.1]Heptan-2-yl, 3, 6-diazabicyclo [3.1.1]Heptan-3-yl, 3-azabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-3-yl, 2, 5-dinitrogenHeterobicyclo [2.2.2]Octan-2-yl, and azaspirocyclic groups (e.g. 3-azaspiro [5.5 ]]Undec-3-yl). The heterocyclic group may be unsubstituted or substituted as well defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
The term "nitrogen-containing monocyclic heterocyclyl", as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) monocyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) monovalent cyclic hydrocarbon groups containing one nitrogen atom and optionally containing one or more heteroatoms (e.g. containing 1 to 5, 1 to 4, 1 to 2 or 1) independently selected from sulfur, oxygen and nitrogen. Representative examples of nitrogen-containing monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepin-1-yl), and diazepinyl. The nitrogen-containing monocyclic heterocyclic group may be unsubstituted or substituted (e.g., mono-, di-, tri-, or polysubstituted) as well-defined, wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-orAny combination.
The term "nitrogen-bridged heterocyclyl", as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) tricyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) monovalent cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g. 1 to 5, 1 to 4, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Tricyclic heterocyclyl groups include bridged heterocyclyl groups such as, but not limited to, 6-azabicyclo [3.1.1]Heptan-3-yl, 2, 5-diazabicyclo [2.2.1]Heptan-2-yl, 3, 6-diazabicyclo [3.1.1]Heptan-3-yl, 3-azabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octane-8-yl, 3, 8-diazabicyclo [3.2.1]Octan-3-yl and 2, 5-diazabicyclo [2.2.2]Octane-2-yl. The nitrogen-containing bridged heterocyclic group may be unsubstituted or substituted as well defined (e.g., mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
The term "-O-optionally substituted heterocyclyl", as used herein, alone or in combination, refers to a group in which an optionally substituted heterocyclyl is attached to an oxygen atom. Alternatively, the term "-O-optionally substituted heterocyclyl" is a 4-to 20-membered monocyclic or bicyclic heterocyclyl containing, for example, one or more, for example 1-4 or 1, 2, 3 or 4, heteroatoms selected from nitrogen, oxygen and sulfur. Including but not limited to azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thioMorpholino, dioxacyclohexyl, azepanyl, diazepinyl (e.g. 1, 4-diazepin-1-yl), azetidinyl, diazinooctyl, azabicyclo [3.1.1 ]]Heptyl and azabicyclo [2.2.1]Heptyl and azabicyclo [3.2.1 ]Octyl and azabicyclo [2.2.2]Octyl, diazabicyclo [3.1.1]Heptyl, diazabicyclo [2.2.1]Heptyl, diazabicyclo [3.2.1]Octyl radicals (e.g. 3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) diazabicyclo [2.2.2]Octyl radicals (e.g. 2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl). Herein, the heterocyclyl is optionally substituted with a C selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
The term "heterocyclylene" or "heterocycloalkylene", as used herein, alone or in combination, refers to a 3 to 20 membered monocyclic, bicyclic, or tricyclic saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. In some embodiments, "heterocyclyl" may refer, for example, to a 3-to 15-membered (alternatively 3-to 14-membered, 3-to 12-membered, 3-to 11-membered, 3-to 10-membered, 3-to 9-membered, 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, 3-to 5-membered, or 4-to 9-membered) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1-5 or, 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of monocyclic heterocyclylene include, but are not limited to, azetidinylene, oxetylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranyl, tetrahydrothiophenylene, tetrahydrothiopyranyl, oxazolylene Alkyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and diazepanyl (e.g., 1, 4-diazepanyl, 4, 5-diazepanyl, 1, 3-diazepanyl). Bicyclic heterocyclylene and tricyclic heterocyclylene include bridged, fused and spiro-ylene groups, for example, but not limited to, representative examples include, but are not limited to, 6-azabicyclo [3.1.1]Heptane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 3, 6-diazabicyclo [3.1.1 ]]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 2, 5-diazabicyclo [2.2.2]Octane subunit, and azaspiro-cyclic groups (e.g. 3-azaspiro [5.5 ]]Undecylen). The heterocyclic group may be unsubstituted or substituted as well defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
The term "nitrogen-containing monocyclic heterocyclylene" as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) monocyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon groups containing one nitrogen atom and optionally containing one or more (e.g. containing 1 to 5, 1 to 4, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Representative examples of nitrogen-containing monocyclic heterocyclylene groups include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl,Azepine, diazepan, azepine, and diazinon. The nitrogen-containing monocyclic heterocyclylene may be unsubstituted or substituted as well defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
The term "nitrogen-containing bridged heterocyclyl", as used herein, alone or in combination, refers to a 3 to 20 membered (optionally 3 to 15 membered, 3 to 14 membered, 3 to 12 membered, 3 to 11 membered, 3 to 10 membered, 3 to 9 membered, 3 to 8 membered, 3 to 7 membered, 3 to 6 membered, 3 to 5 membered, or 4 to 9 membered) tricyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one nitrogen atom and optionally containing one or more (e.g. 1 to 5, 1 to 4, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen. Tricyclic heterocyclylene groups include bridged heterocyclylene groups such as, but not limited to, 6-azabicyclo [3.1.1]Heptane subunit, 2, 5-diazabicyclo [2.2.1]Heptane subunit, 3, 6-diazabicyclo [3.1.1 ]]Heptanylene, 3-azabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit, 3, 8-diazabicyclo [3.2.1]Octane subunit and 2, 5-diazabicyclo [2.2.2 ]Octane subunit. The nitrogen-containing bridged heterocyclyl may be unsubstituted or substituted as well defined (e.g. mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
The term "alkynylene" as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical containing 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, more preferably 2) carbon atoms having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds. Examples of alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene and 1, 3-dialynylene.
The term "alkynyl", as used herein, alone or in combination, refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, more preferably 2) carbon atoms having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds. "C 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1, 3-dialkynyl.
The term "alkenylene", as used herein, alone or in combination, refers to a straight or branched chain divalent hydrocarbon radical containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. Examples of alkenylene groups include, but are not limited to, vinylidene (e.g., -ch=ch-), 1-propenylene, allylene, 1-butenylene, 2-butenylene, 3-butenylene, isobutenylene, pentenylene, n-penta-2, 4-dienylene, 1-methyl-but-1-enylene, 2-methyl-but-1-enylene, 3-methyl-but-1-enylene, 1-methyl-but-2-enylene, 2-methyl-but-2-enylene, 3-methyl-but-2-enylene, 1-methyl-but-3-enylene, 2-methyl-but-3-enylene, 3-methyl-but-3-enylene, and hexenylene.
The term "alkenyl" as used herein, alone or in combination, refers to a straight or branched chain monovalent hydrocarbon radical containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5, or 2 to 4, 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. "C 2-6 Examples of alkenyl "include, but are not limited to, vinyl (e.g., CH 2 =ch-), 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-buteneAlkenyl, isobutenyl, pentenyl, n-pent-2, 4-dienyl, 1-methyl-but-1-enyl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 1-methyl-but-2-ylidene, 2-methyl-but-2-ylidene, 3-methyl-but-2-ylidene, 1-methyl-but-3-enyl, 2-methyl-but-3-enyl, 3-methyl-but-3-enyl, and hexenyl.
As used herein, the term "Borneolum Syntheticum" or "bornane" (also known as 1, 7-trimethylyclo [ 2.2.1)]A heptane; camphane; born ane) has a definition known to those skilled in the art. As used herein, the term "bornyl" or "borneol" refers to a monovalent radical of a bornane, i.e., the radical remaining after any hydrogen in the bornane has been removed. Representative examples of "ice flakes" include, but are not limited to, 1, 7-trimethylbicyclo [2.2.1]Heptan-2-yl, 1, 7-trimethylbicyclo [2.2.1]Heptan-3-yl, 1, 7-trimethylbicyclo [2.2.1]Heptane-4-yl, 1, 7-trimethylbicyclo [2.2.1]Heptane-5-yl, or 1, 7-trimethylbicyclo [2.2.1]Heptane-6-yl,
In this context, the term "bicyclo [2.2.1] heptane" (also known as bicyclo [2.2.1] heptane) or "norbornane" has the definition known to the person skilled in the art. As used herein, "bicyclo [2.2.1] heptyl" or "norbornyl" refers to a monovalent group of bicyclo [2.2.1] heptane, i.e., the group remaining after any hydrogen in the bicyclo [2.2.1] heptane has been removed. Representative examples of "bicyclo [2.2.1] heptanyl" include, but are not limited to, bicyclo [2.2.1] heptan-2-yl, bicyclo [2.2.1] heptan-3-yl, bicyclo [2.2.1] heptan-4-yl, bicyclo [2.2.1] heptan-5-yl, or bicyclo [2.2.1] heptan-6-yl.
The term "bicyclo [2.2.1] heptene" is also referred to herein as bicyclo [2.2.1] thiophene) and has a definition known to those skilled in the art. As used herein, "bicyclo [2.2.1] heptenyl" refers to a monovalent group of a bicyclo [2.2.1] heptene, i.e., the group remaining after any hydrogen in the bicyclo [2.2.1] heptene is removed. Representative examples of "bicyclo [2.2.1] heptenyl" include, but are not limited to, bicyclo [2.2.1] hept-5-en-2-yl, bicyclo [2.2.1] hept-5-en-3-yl, or bicyclo [2.2.1] hept-5-en-7-yl.
In this context, the term "adamantane" (also known as Tricyclo [3.3.1.1 ] 3,7 ]decane) has a definition known to those skilled in the art, the structural formula of which is for example as follows:
herein, "adamantyl" refers to a monovalent group of adamantane, i.e., a group remaining after any hydrogen in adamantane is removed. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl, or 10-adamantyl.
In this context, the term "noradamantane" (also known as noramantadine) has a definition known to those skilled in the art, the structural formula of which is for example as shown below: 
In this context, "noradamantyl" refers to a monovalent group of noradamantane, i.e., the group remaining after any hydrogen in the noradamantane has been removed. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, or 9-adamantyl.
In this context, the term "amantadine" has the definition known to the person skilled in the art, i.e. refers to an adamantane having an amino substituent, wherein the amino group may replace a hydrogen on a carbon at any position of the adamantane. An example of "amantadine" may be adamantan-1-amine (corresponding to the English culture academic name adamantan-1-amine or Tricyclo [3.3.1.1 ] 3,7 ]decan-1-amine; CAS 768-94-5) of the formula
In the present disclosureThe term "leaving group" used alone or in combination is a term well known to those skilled in the art and may also be referred to as a leaving group, a fragment of a molecule (ionic or neutral) that carries a pair of electrons away from a reactant in a chemical reaction, and is used in nucleophilic substitution reactions and elimination reactions. Common ionic leaving groups have Cl - 、Br - 、I - And sulfonates (e.g. p-toluenesulfonate, tsO) - ) Neutral molecular leaving groups are water, ammonia and alcohols. In the present disclosure, one skilled in the art can select an appropriate leaving group as desired, such as, but not limited to, -N 3 Halogen, methanesulfonyloxy (MsO-), trifluoromethanesulfonyl oxy (TfO-) or p-toluenesulfonyloxy (TsO-), and the like.
Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula (I), formula (II) or formula (III) are also encompassed within the scope of the present disclosure.
In all embodiments of the present disclosure, the salt or pharmaceutically acceptable salt of the compound of formula (I), formula (II) or formula (III) refers to non-toxic inorganic or organic acid and/or base addition salts. Examples include: sulfate, hydrohalate (including hydrochloride, hydrobromide), citrate, maleate, mesylate, citrate, lactate, L-tartrate, fumarate, L-malate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate, mesylate, or p-toluenesulfonate, and the like.
By "pharmaceutically acceptable carrier" is meant a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that carries or transports the compounds useful in the present disclosure into a patient or to a patient so that they can perform their intended function. Typically, such constructs are carried or transported from one organ or body part to another organ or body part. The carrier is compatible with the other ingredients of the formulation, including the compounds useful in this disclosure, and not deleterious to the patient, and must be "acceptable". Some examples of materials that may be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical formulations.
The term "room temperature" of the present disclosure refers to the temperature of the surrounding environment, e.g., 20-30 ℃.
Herein, "stereoisomers" refer to compounds having the same chemical structure, but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.
In this context, the term "chiral" is a molecule having properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
In this context, the term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
In this context, the term "diastereoisomer" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
Examples
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The present invention may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the present invention. While the invention will be described in conjunction with the specific embodiments, it will be understood that they are not intended to limit the invention to these embodiments.
The following abbreviations are used throughout the specification and examples:
ACN acetonitrile
AcOH acetic acid
AcOK potassium acetate
Bn Benzyl (Benzyl)
Boc t-Butoxycarbonyl group
Brettphos Pd G3 methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -)
Biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II)
Brettphos 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-I-propyl-11' -biphenyl BINAP 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine
BPO dibenzoyl peroxide
CataCXium A Pd G 3 Methanesulfonic acid [ n-butylbis (1-adamantyl) phosphine](2-amino-1, 1' -biphenyl-2-yl) palladium (II) Cbz benzyloxycarbonyl
Con. Concentration
DCE 1, 2-dichloroethane
DCM dichloromethane
DEA diethylamine
DIAD diisopropyl azodicarboxylate
DIEA N, N-diisopropylethylamine
DMA N, N-dimethylacetamide
DMAP 4-dimethylaminopyridine
DME methyl ether
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DIPEA N, N-diisopropylethylamine
EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ESI electrospray ionization
equivalent of equiv
EtOH ethanol
EtOAc or EA ethyl acetate
HATU 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate HPLC high performance liquid chromatography
HRMS high resolution mass spectrometry
IPA isopropyl alcohol
LC-MS liquid chromatography-mass spectrometry
LiHMDS hexamethyldisilyl lithium amide
LRMS low resolution mass spectrometry
LC liquid chromatography
Me methyl group
MeCN acetonitrile
MeOH methanol
MOMO-methoxy-MS mass spectrum
MsO-methanesulfonyloxy
NaHMDS bis (trimethylsilyl) amide sodium
NBS N-bromosuccinimide
NMI N-methyl swooshing
1 H NMR hydrogen Spectroscopy
HFIP hexafluoroisopropanol
MeO-methoxy group
o/n overnight
PCC pyridinium chlorochromate salt
Pin 2 B 2 Diboric acid pinacol ester
PyBOP hexafluorophosphate benzotriazol-1-yl-oxy-tripyrrolidinylphosphine
Ruphos Pd G3 methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-)
1,1' -Biphenyl-2-yl) Palladium (II) (CAS number 1445085-77-7)
rt room temperature
tBu t-butyl
tBuona sodium tert-butoxide
TBSCl tertiary butyl dimethyl chlorosilane
TCFH N, N, N ', N' -tetramethyl chloroformidine hexafluorophosphate
TEA triethylamine
TFA trifluoroacetic acid
T f O-trifluoromethanesulfonyl oxy
Tf 2 O-trifluoromethanesulfonic anhydride
THF tetrahydrofuran
THP tetrahydropyranyl
TLC thin layer chromatography
TMS trimethylsilyl group
TsO-p-toluenesulfonyloxy
TsOH para-toluene sulfonic acid
Xantphos or Xphos 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthenes
In the present invention, 1 the H NMR spectrum was measured using a Bruker-500MHz NMR apparatus using a CD containing 0.1% TMS as an internal standard 3 OD (δ=3.31 ppm) as solvent; or CDCl containing 0.1% TMS as an internal standard 3 (δ=7.26 ppm) as solvent; or DMSO-d containing 0.03% TMS (as internal standard) 6 (δ=2.50 ppm) as solvent; LRMS spectra were measured on an AB Triple 4600 mass spectrometer, HPLC preparations on a SHIMADZU LC-20AP type instrument, and HPLC purities on a SHIMADZU LC-30AP or Waters 1525 type instrument. All reactions were carried out under an air atmosphere unless specifically indicated; the reaction was followed by TLC or LC-MS.
The solvent and reagent treatments were as follows:
the solvent DCM, DMF, NMP, absolute EtOH, absolute MeOH and the like used in the reaction can be purchased from commercial sources;
HPLC preparation is carried out using preparation grade CH 3 CN and deionized water;
unless otherwise indicated, such as norimatinib, dasatinib intermediate N- (2-chloro-6-methylphenyl) -2- [ (6-chloro-2-methyl-4-pyrimidinyl) amino]-5-thiazolecarboxamide, primary Shu Ti Ni intermediate 7- (3-chloropropoxy) -4- [ (2, 4-dichloro-5-methoxyphenyl) amino]PBM or PBM-R in the equation (II) of-6-methoxy-3-cyanoquinoline f Partially corresponding compounds, and variousLength carbon chain linking unit linker (including for forming R 5 Or R is 6 Compounds of the indicated groups), as well as other reagents and pharmaceuticals, are commercially available from commercial sources, either directly or synthetically, using methods known in the art.
The materials and reagents used in the examples below, unless otherwise indicated, are all commercially available for direct use or may be synthesized using or according to methods known in the art.
General synthetic method
The compounds described in this disclosure and/or pharmaceutically acceptable salts thereof can be synthesized using commercially available starting materials by synthetic techniques known in the art. The synthetic schemes described below exemplify the preparation of most compounds. The starting materials or reagents used in each scheme are commercially available or can be prepared by methods known to those skilled in the art. Salts, racemates, enantiomers, phosphates, sulphates, hydrochlorides and prodrug forms of the compounds of formula (I), formula (II) of the present disclosure may be prepared by those skilled in the art according to conventional techniques in the art.
General preparation of intermediate compound method 1:
general preparation of intermediate compound method 2:
general preparation of intermediate compound method 3:
in scheme 3, X of the substrate amine used in step 2 9 And X 10 The same or different and each independently represents N or CH. R is R f1 Is a divalent radical R with a compound of the formula (II) f Corresponding monovalent radicals. For example, R f1 represents-OH, -NH (R) g )-、-NHC(O)-R h -W 5 -H、-C(O)NH-R h -W 5 -H、-NHC(O)-W 5 -H、-C(O)NH-W 5 -H、-O-R h -W 5 -H、-O-W 5 -H、-O-R h -NH(R i )、-N(R g )-R h -NH(R i )、-W 5 -H、-W 5 -NH(R g )、-N(R g )-W 5 -H、-N(R g )-W 5 -NH(R i )、-R h -W 5 -H、-R h -C(O)-W 5 -H、-C(O)-W 5 -H、-R h -C(O)NH-R j -W 5 -H、-R h -NHC(O)-R j -W 5 -H、-R h -NH(R i ) Or (b)
Wherein R is g 、R h 、R i 、R j And W 5 As defined herein for compounds of formula (II) and embodiments thereof. It is to be understood that when the radical R f1 When active hydrogen is contained, which may participate in the reaction of step 2, the active hydrogen may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. For example when R f1 When piperidinyl or piperazinyl is represented, the hydrogen on N may be protected with a conventional protecting group such as Boc or the like. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
The palladium catalyst and phosphine ligand used in step 2 of scheme 3 may be conventional and suitable for coupling reactions. The conventional palladium catalysts used for the coupling reaction are of a wide variety, such as palladium acetate (Pd (OAc) 2 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Diphenylphosphino ferrocene palladium dichloride, tetraphenylphosphine palladium, diphenylphosphine palladium dichloride, palladium carbon, and the like. The phosphine ligand may be conventional Xantphos, BINAP or the like.
In step 1 of scheme 3, 2, 4-dichloro-5-methylpyrimidine (6.78 g,41.608 mmol) was added to 3-amino-N- (tert-butyl) benzenesulfonamide (9.50 g,41.608 mmol) in MeOH/H 2 O (400 mL) and the reaction was stirred at 80℃for 18 hours. LCMS detection showed the reaction was complete. The mixture was cooled to room temperature, a large amount of white solid precipitated, filtered, and the filter cake washed with methanol/water (50 mL, 1:1) and dried under high vacuum at 50deg.C to give the white solid compound N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide (8.00 g,22.544mmol, 54.18%). LCMS (ESI): calculated (M) 354.09, found (M+H) + 355.10。
In step 2 of scheme 3, cs is added to a solution of N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide (1 equiv) and the corresponding substrate amine (1.3 equiv) in dioxane (50 mL) 2 CO 3 Suitable palladium catalyst/phosphine ligands. The reaction was stirred at 100℃for 4 hours. The reaction solution was diluted with ethyl acetate and saturated NaCl solution, and was treated with Na 2 SO 4 Drying and vacuum concentration to obtain crude product. The crude product was purified by flash column chromatography on silica gel (eluent (v/v): etOAc/pe=0/1-1/4) to give the title compound.
General preparation of intermediate compound method 4:
general preparation of intermediate compound method 5:
in scheme 5, the substrate amine (R b3 ) t3 Ring B, (R) b4 ) t4 Q of the substrate acid used 1 And (R) b5 ) t5 As defined in formula (PBM-7-1A-1) and its various embodiments. R of the substrate acid used f1 Is a divalent radical R with a compound of the formula (II) f Corresponding monovalent radicals. Example(s)For example, R f1 represents-OH, -NH (R) g )-、-NHC(O)-R h -W 5 -H、-C(O)NH-R h -W 5 -H、-NHC(O)-W 5 -H、-C(O)NH-W 5 -H、-O-R h -W 5 -H、-O-W 5 -H、-O-R h -NH(R i )、-N(R g )-R h -NH(R i )、-W 5 -H、-W 5 -NH(R g )、-N(R g )-W 5 -H、-N(R g )-W 5 -NH(R i )、-R h -W 5 -H、-R h -C(O)-W 5 -H、-C(O)-W 5 -H、-R h -C(O)NH-R j -W 5 -H、-R h -NHC(O)-R j -W 5 -H、-R h -NH(R i ) Or (b)
Wherein R is g 、R h 、R i 、R j And W 5 As defined herein for compounds of formula (II) and embodiments thereof. It is to be understood that when the radical R f1 When an active hydrogen or a reactive group is contained which can participate in the reaction of scheme 5, the active hydrogen or the reactive group may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. For example when R f1 When piperidinyl or piperazinyl is represented, the hydrogen on N may be protected with a conventional protecting group such as Boc or the like. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
In scheme 5, the substrate acid (1 equiv) and substrate amine (1 equiv) were dissolved in DMF, HATU (1.5 equiv) and DIEA (5 equiv) were added, and then reacted at room temperature for 30 minutes. LC-MS detected completion of the reaction. Water was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. The organic phase is washed with saturated common salt water and concentrated to obtain crude product. The crude product was purified by column chromatography (eluent (v/v): DCM/meoh=100/1) to give the title compound.
General preparation of intermediate (JQ-1 derivative):
step 1:
(S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetic acid (1 equiv) and the corresponding amine (1.2 equiv) were dissolved with HATU (2 equiv) in 10mL DCM, DIEA (5 equiv) was added and reacted at room temperature for 1H. The reaction solution was washed with 10mL of water 2 times, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the Boc intermediate compound.
Step 2:
the Boc intermediate compound obtained in step 1 was dissolved in HCl/1, 4-dioxane (dioxane) and reacted at room temperature for 1h. The reaction solution was distilled under reduced pressure to remove the solvent, whereby the objective compound was obtained.
General preparation of compounds of formula (I) method 1:
General preparation of compounds of formula (I) method 2:
in scheme 8, a is as defined for compounds of formula (I) herein.
Step 1: 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (1 equiv) was dissolved in 4mL of DMF, the corresponding amine (1.1 equiv) and N, N-diisopropylethylamine (3 equiv) were added, then reacted overnight at room temperature, LCMS detected completion of the reaction, the reaction was extracted with ethyl acetate, the organic phases were combined and washed with water, the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, isolated using column chromatography (DCM: etoac=2:1 to 1:1) to afford Boc intermediate compound.
Step 2, dissolving the product of the previous step in5mL of DCM to which CF is added 3 CO 2 H (1 mL), then reacting for 3H at room temperature, and concentrating under reduced pressure to obtain a trifluoroacetate product of the target compound.
Depending on the target compound, the reaction substrate amine in scheme 8, reaction conditions (including reaction amount, temperature, time, etc.), post-treatment, etc. may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. In some embodiments, the reaction substrate amine may be a fatty amine (e.g., HNR 7 R 8 ) Or a group W 1 Corresponding structures (e.g
A nitrogen-containing monocyclic heterocycle, a nitrogen-containing bridged heterocycle, a nitrogen-containing spiro heterocycle, or a nitrogen-containing condensed heterocycle; or->
Wherein each ring W 3 Identical or different and each independently represents an optionally substituted nitrogen-containing heterocyclic group, t represents an integer 1 or 2, and ring W 4 Represents an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclyl group). It will be appreciated that when the reaction substrate amine contains additional active hydrogen or reactive groups that may participate in the step 1 reaction of scheme 6, the active hydrogen or reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. For example, when the reaction substrate amine represents piperazine, a conventional protecting group such as Boc or the like may be used to protect the hydrogen on one of the N of piperazine. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
General preparation of compounds of formula (I) method 3:
in scheme 9, br can be in the 4-, 5-, 6-, or 7-position on the phenyl ring of the isoindolinyl group, and the hydroxymethyl group of the resulting product is also correspondingly in the 4-, 5-, 6-, or 7-position on the phenyl ring of the isoindolinyl group. A is as defined for compounds of formula (I) herein. (R) ba ) n Represents the benzene ring is substituted by n R ba Substituted, each R ba Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer of 0, 1, 2, or 3.
General preparation of compounds of formula (I) method 4:
general preparation of compounds of formula (II) method 1:
scheme 11 wherein the substrate amine is PBM-R of the compound of formula (II) f A part of the corresponding compound containing an aliphatic or heterocyclic amine (e.g. a nitrogen-containing monocyclic heterocycle, a nitrogen-containing bridged heterocycle, a nitrogen-containing spiro heterocycle or a nitrogen-containing fused heterocycle) group or an amino group, and a of the other substrate 1 is as defined in the compound of formula (II) herein, the group Z may be a group such as Br, cl, I, OMs, OTs or OTf. (R) ba ) n Represents the benzene ring is substituted by n R ba Substituted, each R ba Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer0. 1, 2, or 3.
Step 1: (1) When the group Z is an OMs, OTs or OTf group, the substrate alcohol may be esterified with, for example, msCl (methanesulfonyl chloride), tsCl (p-toluenesulfonyl chloride) or TfCl (trifluoromethanesulfonyl chloride) under basic conditions (e.g., TEA, DIEA) to give the corresponding target intermediate 1. Alternatively (2) when the group Z is Br, cl or I, the substrate alcohol may be reacted with, for example, CBr 4 /PPh 3 Halogenation of DCM gave the corresponding target intermediate 1.
Step 2: substrate amine (1 equiv) and target intermediate 1 (1.2 equiv) were dissolved in DMF. Subsequently, DIEA (5 equiv) was added to the mixed solution. The reaction solution was stirred at room temperature to 80℃for 0.5-24 hours. LCMS detects the end of the reaction. The reaction solution was filtered, and the filtrate was separated and purified by preparative HPLC to obtain the objective compound.
General preparation of compounds of formula (II) method 2:
the substrate alcohol/phenol in scheme 12 has the formula PBM-OH, wherein PBM, a are as defined in the compounds of formula (II) herein.
The substrate alcohol (1 equiv) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (1.2 equiv) were dissolved in DMF and K was added 2 CO 3 (5 equiv). The reaction solution is stirred and reacted for 0.5 to 48 hours at the temperature of 50 to 80 ℃. LCMS detects the end of the reaction. The reaction solution was filtered, and the filtrate was separated and purified by preparative HPLC to obtain the objective compound.
General preparation of compounds of formula (II) method 3:
scheme 13 wherein the substrate amine is PBM-R with a compound of formula (II) f Partially corresponding compounds, wherein R f Containing fatty or heterocyclic amines (e.g. nitrogen-containing monocyclic heterocycles, nitrogen-containing bridged heterocycles, nitrogen-containing spiro heterocycles, or containingNitrogen-condensed heterocycle) group or amino group. A. PBM, R f 、R 6 As defined herein for compounds of formula (II). It is to be understood that when the radical R 6 Containing additional reactive groups (e.g., -NH or-NH) that may participate in the reaction of scheme 13 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups.
Dissolving corresponding aldehyde or carbonyl compound (1.0 equiv) and substrate amine (1.0 equiv) in dichloromethane, adding appropriate amount of acetic acid, reacting at room temperature for 30 min, then adding sodium cyanoborohydride (3.0 equiv) and continuing at room temperature, detecting reaction completion by LCMS, C 18 And (3) separating by reverse phase column chromatography to obtain the final target compound.
General preparation of intermediate compound method 6:
(R) of Compound 1 in scheme 14 m1 ) s1 Represents a benzene ring optionally substituted by s 1R m1 Substituted, each R m1 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl (e.g. methyl or ethyl), halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy (e.g. methoxy or isopropoxy), halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, s1 represents an integer 0, 1, 2, 3 or 4, Y 1 Represents halogen (e.g. fluorine, chlorine or bromine) and Y 2 、Y 3 、Y 4 And Y 5 Each independently represents N or CH, and Y 2 、Y 3 、Y 4 And Y 5 And are not simultaneously N. Ring W 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Contains additional ginsengReactive groups reactive with scheme 14 (e.g., ring W 6 -R n1 Represents- -NH- -or- -NH 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups.
Depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 14 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. In scheme 14, the substitution reaction of step 1 or the palladium catalyzed coupling reaction may be conventional techniques and methods well known to those skilled in the art. When step 1 is a substitution reaction, Y 1 Represents fluorine, compounds 1 and 2 are reacted under basic conditions (e.g., K 2 CO 3 ) And (3) carrying out the reaction. When step 1 is a palladium-catalyzed coupling reaction, Y 1 Meaning bromine, the palladium catalyst and phosphine ligand used may be conventional ones suitable for coupling reactions. The conventional palladium catalysts used for the coupling reaction are of a wide variety, such as palladium acetate (Pd (OAc) 2 ) Tris (dibenzylideneacetone) dipalladium (Pd) 2 (dba) 3 ) Diphenylphosphino ferrocene palladium dichloride, tetraphenylphosphine palladium, diphenylphosphine palladium dichloride, palladium carbon and the like. The phosphine ligand may be conventional Xantphos, BINAP or the like. In scheme 14, the reduction reaction of step 2 may be conventional techniques and methods well known to those skilled in the art, such as H 2 Pd/C; or Fe/NH 4 Cl/MeOH。
General preparation of intermediate compound method 7:
general preparation of intermediate compound method 8:
(R) of the Compound of scheme 16 m1 ) s1 Represents a benzene ring optionally substituted by s 1R m1 Substituted, each R m1 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl (e.g. methyl or ethyl), halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy (e.g. methoxy or isopropoxy), halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, Y 1 Represents halogen (e.g. fluorine, chlorine or bromine) and Y 2 、Y 3 、Y 4 And Y 5 Each independently represents N or CH, and Y 2 、Y 3 、Y 4 And Y 5 And are not simultaneously N. Ring W 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) that may participate in the reaction of scheme 16 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
Depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 16 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. The substitution or coupling reactions in scheme 16 may be conventional techniques and methods well known to those skilled in the art. For example, the substitution reaction may be carried out in the presence of triethylamine/isopropanol, or p-toluenesulfonic acid/n-butanol, or DIEA/ethanol, or NaHMDS, or NaI/DIEA/DMF under heating; the coupling reaction can be In Brettphos Pd G3/Brettphos ligand/Cs 2 CO 3 Is carried out under heating in the presence of (a).
General preparation of intermediate compound method 9:
compound 8 of step 1 of scheme 17 can be prepared according to scheme 15.
General preparation of intermediate compound method 10:
(R) of the Compound in scheme 18 m1 ) s1 Represents a benzene ring optionally substituted by s 1R m1 Substituted, each R m1 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl (e.g. methyl or ethyl), halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy (e.g. methoxy or isopropoxy), halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, s1 represents an integer 0, 1, 2, 3 or 4, Y 1 Represents halogen (e.g. fluorine, chlorine or bromine) and Y 2 、Y 3 、Y 4 And Y 5 Each independently represents N or CH, and Y 2 、Y 3 、Y 4 And Y 5 And are not simultaneously N. Ring W 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) that may participate in the reaction of scheme 18 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups.
Depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 18 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. The substitution or coupling reactions in scheme 18 may be conventional techniques and methods well known to those skilled in the art. For example, the substitution reaction may be carried out in the presence of triethylamine/isopropanol, or DIEA/ethanol, or NaHMDS, or NaI/DIEA/DMF under heating; the coupling reaction can be carried out in Brettphos Pd G3/Brettphos ligand/Cs 2 CO 3 Is carried out under heating in the presence of (a).
General preparation of intermediate compound method 11:
(R) of the Compound of scheme 19 m1 ) s1 Represents a benzene ring optionally substituted by s 1R m1 Substituted, each R m1 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl (e.g. methyl or ethyl), halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy (e.g. methoxy or isopropoxy), halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, Y 1 Represents halogen (e.g. fluorine, chlorine or bromine) and Y 2 、Y 3 、Y 4 And Y 5 Each independently represents N or CH, and Y 2 、Y 3 、Y 4 And Y 5 And are not simultaneously N. Ring W 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) which may participate in the reaction of scheme 19 2 ) When it is, the technology in the fieldTechniques and methods well known to the skilled artisan, such as protecting groups, protect the reactive groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
Depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 19 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. The substitution reaction in scheme 19 may be conventional techniques and methods well known to those skilled in the art. For example, the substitution reaction may be carried out in the presence of triethylamine/isopropanol, or DIEA/ethanol, or NaI/DIEA/DMF under heating.
General preparation of intermediate compound method 12:
General preparation of intermediate compound method 13:
general preparation of intermediate compound method 14:
general preparation of intermediate compound method 15:
general preparation of intermediate compound method 16:
general preparation of intermediate compound 17:
ring W of the compound of scheme 25 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) which may participate in the reaction of scheme 25 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
Depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 25 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound.
General preparation of intermediate compound method 18:
ring W of the compound of scheme 26 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) that may participate in the reaction of scheme 26 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
General preparation of intermediate compound method 19:
ring W of the compound of scheme 27 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) that may participate in the reaction of scheme 27 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
General preparation of intermediate compound method 20:
ring W of the compound of scheme 28 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl).It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) that may participate in the reaction of scheme 28 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
Depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 28 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. The reductive amination reaction in scheme 28 can be conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction may be carried out in the presence of sodium triacetoxyborohydride/1, 2-dichloroethane, or sodium cyanoborohydride/1, 2-dichloroethane, at room temperature.
General preparation of intermediate compound method 21:
(R) of the Compound of scheme 29 m1 ) s1 Represents a benzene ring optionally substituted by s 1R m1 Substituted, each R m1 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl (e.g. methyl or ethyl), halo C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy (e.g. methoxy or isopropoxy), halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, Y 1 Represents halogen (e.g. fluorine, chlorine or bromine) and Y 2 、Y 3 、Y 4 And Y 5 Each independently represents N or CH, and Y 2 、Y 3 、Y 4 And Y 5 And are not simultaneously N. Ring W 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups (e.g., -NH-or-NH-) which may participate in the reaction of scheme 29 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions, such as hydrochloric acid, or trifluoroacetic acid.
General preparation of intermediate compound method 22:
Ring W of the compound of scheme 30 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that ring W in the starting compound of scheme 30, step 1 6 -R n1 Containing additional reactive groups (e.g. -NH-or-NH) 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions (e.g., concentrated sulfuric acid, etc.) of step 2.
General preparation of intermediate compound method 23:
general preparation of intermediate compound method 24:
general preparation of intermediate compound method 25:
general preparation of intermediate compound method 26:
ring W of the compound of scheme 34 6 Ring W 7 、t1、t2、(R a2 ) m2 、(R a3 ) m3 As defined herein for compounds of formula (II). R is R n1 Represents Boc, H or-NHR g Wherein R is g Represents hydrogen or C 1-6 Alkyl (e.g., methyl or ethyl). It will be appreciated that when ring W 6 -R n1 Containing additional reactive groups capable of participating in the reaction (e.g. -NH-or-NH 2 ) When present, the reactive groups may be protected by techniques and methods well known to those skilled in the art, such as protecting groups. Removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions (e.g., concentrated sulfuric acid, etc.).
General preparation of intermediate compound method 27:
general preparation of intermediate compound method 28:
general preparation of intermediate compound 29:
removal of the protecting group may be accomplished by techniques and methods well known to those skilled in the art, for example, removal of the protecting group Boc may be accomplished under acidic conditions (e.g., concentrated sulfuric acid, etc.).
General preparation of intermediate compound method 30:
depending on the target compound, the reaction substrates, reaction conditions (including reaction amounts, temperature, time, etc.), post-treatments, etc. in the scheme 38 may be appropriately modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound. The amide condensation reaction in scheme 38 may be conventional techniques and methods well known to those skilled in the art. For example, the amide condensation reaction may be carried out in the presence of HATU/DIEA/DMF or HOAt/EDCI/TEA/DCM at room temperature.
General preparation of intermediate compound method 31:
general preparation of intermediate compound method 32:
general preparation of intermediate compound method 33:
general preparation of intermediate compound method 34:
general preparation of intermediate compound 35:
General preparation of intermediate compound method 36:
general preparation of intermediate compound method 37:
general preparation of intermediate compound method 38:
general preparation of intermediate compound method 39:
general preparation of intermediate compound method 40:
general preparation of intermediate compound method 41:
general preparation of intermediate compound method 42:
general preparation of intermediate compound 43:
general preparation of intermediate compound method 44:
general preparation of intermediate compound method 45:
general preparation of intermediate compound method 46:
general preparation of intermediate compound method 47:
general preparation of compounds of formula (II) method 4:
r of the target product in scheme 56 m -C (O) NH-moiety corresponds to R of the compound of formula (II) herein f Part, wherein R is f A, PBM are as defined for the compounds of formula (II) herein. The condensation reaction in scheme 56 may be conventional techniques and methods well known to those skilled in the art, for example, conventional condensing agents HOAt/EDCI, T may be employed 3 P and the like are carried out under alkaline (e.g., DMAP and the like) conditions at room temperature or under heat.
General preparation of intermediate compound method 48:
the pure enantiomer products were obtained according to scheme 57 and resolved by Supercritical Fluid Chromatography (SFC), respectively. Supercritical Fluid Chromatography (SFC) can be suitably modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound.
General preparation of intermediate compound method 49:
the pure enantiomer products were obtained according to scheme 58 and resolved by Supercritical Fluid Chromatography (SFC), respectively. The conditions of Supercritical Fluid Chromatography (SFC) can be suitably modified and adapted by techniques and methods well known to those skilled in the art to obtain the desired target compound.
General preparation of compounds of formula (II) method 5:
r of substrate amine in scheme 59 bd -NH-R bc -in, a group R bd Represents hydrogen, R bc Represents a nitrogen-containing heterocyclic group; alternatively, R bd And R is bc Together with the nitrogen atom to which they are attached, form a 4-to 15-membered monocyclic, spiro or bridged heterocyclic group or nitrogen-containing fused heterocyclic ring containing 1-2 nitrogen atoms; a is as defined herein for compounds of formula (II); r is R 5 And R is 6 As defined herein for compounds of formula (I); (R) ba ) n Represents the benzene ring is substituted by n R ba Substituted, each R ba Identical or different and each independently represents deuterium, fluorine, hydroxyl with a protecting group, mercapto with a protecting group, nitro, amino with a protecting group, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; n represents an integer of 0, 1, 2, or 3. Groups PBM and W of the other substrate aldehyde 7 As defined herein for compounds of formula (II).
The reductive amination reaction of scheme 59 can be conventional techniques and methods well known to those skilled in the art. For example, the reductive amination reaction may be carried out in the presence of sodium borohydride acetate and 1, 2-dichloroethane at room temperature to 80 ℃.
For example, the corresponding aldehyde (1.0 equiv) and amine (1.0 equiv) are dissolved in dichloromethane, an appropriate amount of acetic acid is added, the reaction is carried out at room temperature for 30 minutes, then sodium cyanoborohydride (3.0 equiv) is added and the reaction is continued at room temperature, and after completion of the LCMS detection reaction, C 18 Separating by reversed phase column chromatography, removing acetonitrile by rotation, and lyophilizing to obtain final target compound.
General preparation of intermediate compound method 50:
general preparation of intermediate compound method 51:
general preparation of intermediate compound method 52:
general preparation of intermediate compound method 53:
general preparation of intermediate compound method 54:
general preparation of intermediate compound method 55:
general preparation of intermediate compound method 56:
depending on the target compound, each of the above schemes and its reaction substrate, reaction conditions (including reaction amount, temperature, time, etc.), post-treatment, etc., may be appropriately modified and adjusted by techniques and methods well known to those skilled in the art to obtain the desired target compound, and the obtained target compound may be further modified by substituents, etc., according to methods well known to those skilled in the art to obtain other target compounds.
Examples
Intermediate example 1: preparation of 1- ((3S, 4R) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
Reference to the procedure of scheme 1 prepares 1- ((3 s,4 r) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine.
Step 1: (3S, 4S) -3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (370 mg,1.69 mmol) was dissolved in anhydrous dichloromethane, DIEA (0.5 ml,3.38 mmol), p-toluenesulfonyl chloride (3836 mg,2.03 mmol) and DMAP (206.16 mg,1.69 mmol) were added sequentially to the reaction solution. The reaction was stirred at room temperature for 18 hours and TLC checked for completion. H for reaction solution 2 O (50 mL) was washed and extracted with DCM (50 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent (v/v): PE/etoac=1/1) to give the compound (3 s,4 s) -3-fluoro-4-p-toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (350 mg, yield 55%) as a white solid.
Step 2: the compound (3S, 4S) -3-fluoro-4-p-toluenesulfonyloxy) piperidine-1-carboxylic acid tert-butyl ester (350 mg,0.94 mmol) was dissolved in anhydrous DMSO (20 mL), and 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] was added to the reaction solution in this order]Pyrimidine-4-amine (284 mg,0.94 mmol) and K 2 CO 3 (3838 mg,2.81 mmol). The reaction was warmed to 85 ℃, stirred for 18 hours, and TLC detected the completion of the reaction. The reaction mixture was cooled to room temperature using H 2 O (100 mL) was washed and extracted with EtOAc (100 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography eluting with DCM/meoh=20/1 to give the compound (3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d) as a white solid]Pyrimidine-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (350 mg, yield 74%). LC/MS (ESI, m/z) 505.3[ M+H ]] + .
Step 3: the compound (3S, 4R) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d)]Pyrimidine-1-yl) -3-fluoropiperidine-1-carboxylic acid tert-butyl ester (350 mg,0.69 mmol) was dissolved in anhydrous DCM (15 mL) and HCl/dioxane (1.7 mL, 4M) was added to the reaction. The reaction was stirred at room temperature for 1 hour and TLC checked for completion. Concentrating the reaction solution under reduced pressure to obtain a white solid target compound 1- ((3S, 4R) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d)]Pyrimidin-4-amine (205 mg, 67% yield). 1 H NMR(400MHz,DMSO)δ8.24(d,J＝5.6Hz,1H),7.69(d,J＝8.6Hz,2H),7.44(dd,J＝8.4,7.6Hz,2H),7.28–7.04(m,5H),5.15–4.76(m,2H),3.34(d,J＝7.3Hz,1H),2.97(d,J＝12.3Hz,1H),2.63(ddd,J＝15.0,12.2,3.5Hz,2H),2.12(dd,J＝12.3,4.1Hz,1H),1.94(d,J＝12.7Hz,1H). 19 F NMR(377MHz,DMSO)δ-185.23(s).LC/MS(ESI,m/z)[M+H] + Calculated, measured 405.2, 405.1.
Intermediate example 2: preparation of 3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine hydrochloride
Preparation of 3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine hydrochloride by the method of reference scheme 2.
Step 1: to a solution of triphenylphosphine (154.59 g,574.1 mmol) in tetrahydrofuran (3L) was added DIAD (117.54 g,581.3 mmol) at 0deg.C. After the addition was complete, the mixture was stirred for 0.5 hours. 2-methylpropan-2-yl 4-hydroxycyclopyridine-1-carboxylic acid ester (118.6 g,589.3 mmol) was then added to the mixture at 0deg.C and stirred for 0.5 h. 3- [4- (phenoxy) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-4-amine (90 g,296.7 mmol) was then added to the reaction solution and the temperature was slowly raised to 25℃and stirred for 16 hours. TLC detection showed the reaction was complete. The reaction mixture was concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography on silica gel (eluent (v/v): PE/etoac=1/0-1/1) to give 4- ((4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) oxy) piperidine-1-tert-butylformate as a white solid (92.0 g,189.3mmol, 63.8%). LCMS (ESI): calculated values: 487.24; found [ m+h ] += 487.30.
Step 2: 4- ((4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d) at 10 DEG C ]Pyrimidin-1-yl) oxy piperidine-1-tert-butyl formate (92.0 g,189.3 mmol) was dissolved in HCl/EtOAc (340 mL, 3M). The mixture was stirred at room temperature for 3 hours. TLC detection showed the reaction was complete. A large amount of white solid precipitated, the solid was filtered off, and the solid was purified with ethyl acetate/petroleum ether (1:8300 ml) was ground and filtered. The solid was dried under high vacuum to give the compound 4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d) as a white solid]Pyrimidin-1-yl) piperidine hydrochloride (60 g,154.957mmol, 52% yield). 1 H NMR (400 MHz, DMSO). Delta.8.25 (s, 1H), 7.69-7.61 (m, 2H), 7.47-7.39 (m, 2H), 7.23-7.09 (m, 6H), 4.98-4.89 (m, 1H), 3.35-3.26 (m, 3H), 2.99 (t, J=12.1 Hz, 2H), 2.35-2.19 (m, 2H), 2.07-1.98 (m, 2H). LCMS (ESI): calculated values: 387.19; actual measurement value [ M+H] + ＝387.20。
Intermediate example 3: preparation of (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (piperazin-1-yl) ethyl) acetamide
Referring to scheme 6, in step 1, (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetic acid (1 equiv) and tert-butyl 4- (2-aminoethyl) piperazine-1-carboxylate (1.2 equiv) were dissolved in 10mL DCM, DIEA (5 equiv) was added and reacted at room temperature for 1H. The reaction solution was washed with 10mL of water 2 times, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent (v/v): DCM/meoh=100/0-10/1) to give the corresponding Boc intermediate compound.
And 2, dissolving the compound obtained in the step 1 in HCl/1, 4-dioxane, and reacting for 1h at room temperature. The solvent was distilled off under reduced pressure to give the title compound (yellow solid, 72mg, yield 53%). LCMS (ESI) m/z C 25 H 31 ClN 7 OS + [M+H] + Calculated, 512.20; found, 512.2.
Intermediate example 4: preparation of (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -1- (piperazin-1-yl) ethan-1-one
Referring to scheme 6, in step 1, (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetic acid (1 equiv) and tert-butyl piperazine-1-carboxylate (1.2 equiv) were dissolved in 10mL DCM, DIEA (5 equiv) was added and reacted at room temperature for 1H. The reaction solution was washed with 10mL of water 2 times, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent (v/v): DCM to DCM/MeOH (10/1)) to give the corresponding Boc intermediate compound.
And 2, dissolving the compound obtained in the step 1 in HCl/1, 4-dioxane, and reacting for 1h at room temperature. The solvent was distilled off under reduced pressure to give the title compound (yellow solid, 260mg, yield 92%). LCMS (ESI) m/z C 23 H 26 ClN 6 OS + [M+H] + Calculated, 469.16; found, 469.1.
Intermediate example 5: preparation of tert-butyl 4- (2- (4-aminophenoxy) ethyl) piperazine-1-carboxylate
Step 1: to a solution of 1- (2-bromoethoxy) -4-nitrobenzene (4.50 g, 18.284 mmol) in N, N-dimethylformamide (100 mL) was added TEA (3.66 g,36.576 mmol) and the reaction mixture was stirred at 60℃for 30 min. TLC detection showed the reaction was complete. The reaction mixture was diluted with EtOAc (100 mL) and ice-water (100 mL). The organic layer was separated. The organic layer was further washed with saturated brine (100 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent (v/v): PE/etoac=1/0-0/1) to give the compound 4- [2- (4-nitrophenoxy) ethyl as a colourless oil]Piperazine-1-carboxylic acid tert-butyl ester (4 g,11.383mmol, yield 62.24%). 1 H NMR(300 MHz,CDCl 3 ) δ8.19 (2 h, m), 6.97 (2 h, m), 4.19 (t, j=5.6; LCMS (ESI) calculated (M) 351.18, found (M+H) + 352.30。
Step 2: to 4- [2- (4-nitrophenoxy) ethyl ]]Piperazine-1-carboxylic acid tert-butyl esterTo a solution of (4.00 g,11.383 mmol) in MeOH (50 mL) was added Pd/C (0.12 g,1.138mmol, 10%) and the reaction was stirred under a hydrogen balloon at room temperature for 16 hours. LCMS detection showed the reaction was complete. The mixture was filtered using a celite bed and washed with methanol (20 mL). The filtrate was concentrated to give tert-butyl 4- (2- (4-aminophenoxy) ethyl) piperazine-1-carboxylate (3.1 g, yield 84.73%) as an off-white solid. LCMS (ESI): calculated (M) 321.42, found (M+H) + 322.20。
Intermediate example 6: preparation of tert-butyl 4- (6-aminopyridazin-3-yl) piperazine-1-carboxylate
Step 1: to a solution of tert-butyl 4- (6-chloropyridazin-3-yl) piperazine-1-carboxylate (3.00 g,10.041 mmol) in toluene (60 mL) was added diphenylazomethine (2.022 mL,12.049 mmol), BINAP (0.06 g,0.100 mmol), cs under argon 2 CO 3 (6.54 g,20.082 mmol) and Pd 2 (dba) 3 (0.46 g,0.502 mmol). The resulting suspension was stirred at 100℃for 16 hours. LCMS detection showed the reaction was complete. The resulting reaction mixture was cooled to room temperature, then filtered through celite, and the celite was washed with ethyl acetate (30 mL). The filtrate was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and the solid was isolated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give tert-butyl 4- (6- ((diphenylmethylene) amino) pyridazin-3-yl) piperazine-1-carboxylate (2.60 g,5.862mmol, yield 58.38%) as a white solid. LCMS (ESI): calculated 443.20; actual measurement value [ M+H] + ＝444.20。
Step 2: to a solution of tert-butyl 4- (6- ((diphenylmethylene) amino) pyridazin-3-yl) piperazine-1-carboxylate (2.60 g,5.862 mmol) in THF (50 mL) was added citric acid/H 2 O (20 mL) and stirred at 20deg.C for 16 h. LCMS detection showed completion of the reaction. The reaction mixture was concentrated in vacuo to remove THF. The aqueous phase obtained is saturated with NaHCO 3 Adjust to ph=8 and extract with EtOAc (100 ml X3). The organic layers were combined and taken up with Na 2 SO 4 Dried, concentrated under reduced pressure to give 4- (6-aminopyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester as a white solid (1.6 g, yield 97.71%). LCMS (ESI): calculated value M:279.20; actual measurement value [ M+H] + ＝280.20。
Intermediate example 7: preparation of N- (tert-butyl) -3- ((5-methyl-2- ((4- (2- (piperazin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-002)
Step 1: tert-butyl 4- (2- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) ethyl) piperazine-1-carboxylate was prepared according to the method of scheme 3, step 2.
Pd was added to a solution of tert-butyl 4- (2- (4-aminophenoxy) ethyl) piperazine-1-carboxylate (2.0 g,6.222 mmol) and N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide (2.87 g,8.089 mmol) prepared in scheme 3 in dioxane (50 mL) under argon 2 (dba) 3 (0.36g，0.622mmol)、Cs 2 CO 3 (4.06 g,12.445 mmol) and 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (0.72 g,1.244 mmol). The reaction was stirred at 100℃for 4 hours. The reaction was diluted with EtOAc (50 mL) and saturated NaCl solution (50 mL). The reaction mixture obtained is subjected to Na 2 SO 4 Drying and vacuum concentration to obtain crude product. The crude product was purified by flash column chromatography on silica gel (eluent (v/v): etOAc/pe=0/1-1/4) to give the compound 4- (2- (4- ((4- ((3- (N- (tert-butyl) aminosulfonyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) ethyl) piperazine-1-carboxylic acid tert-butyl ester (2 g,3.126mmol, 50.24%) as a white solid. LCMS (ESI): calculated (M) 639.20, found (M+H) + 640.20。
Step 2: to a solution of tert-butyl 4- (2- (4- ((4- ((3- (N- (tert-butyl) sulfamoyl) phenyl) amino) -5-methylpyrimidin-2-yl) amino) phenoxy) ethyl) piperazine-1-carboxylate (2 g,3.126 mmol) in DCM (50 mL) was added TFA (10 mL) and the reaction mixture stirred at room temperature for 20 min. LCMS detection showed a reaction junctionA bundle. The reaction mixture was concentrated in vacuo to give the compound N- (tert-butyl) -3- ((5-methyl-2- ((4- (2- (piperazin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide as a white solid (1.20 g, yield 71.13%). 1 H NMR(400MHz,DMSO)δ8.78(s,1H),8.54(s,1H),8.11(s,2H),7.90(s,1H),7.62–7.40(m,5H),6.79(d,1H)J＝9.0Hz,2H),3.99(t,J＝5.9Hz,2H),2.65(dt,J＝11.8,5.3Hz,6H),2.38(s,4H),2.12(s,3H),1.12(s,9H)。LCMS(ESI)：(M+H) + Calculated (M) 540.3, found 540.7.
Intermediate example 8: preparation of N- (tert-butyl) -3- ((5-methyl-2- ((6- (piperazin-1-yl) pyridazin-3-yl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-17)
Referring to the procedure of scheme 3, step 2 and intermediate example 7, the title compound N- (tert-butyl) -3- ((5-methyl-2- ((6- (piperazin-1-yl) pyridazin-3-yl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (552 mg, 66.31%) was prepared as a white solid using intermediate example 6 to give 4- (6-aminopyridazin-3-yl) piperazine-1-carboxylic acid tert-butyl ester and N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide under appropriate conditions as understood in the art. 1 H NMR (400 mhz, dmso) δ9.35 (s, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 8.14 (dd, j=6.9, 2.4hz, 1H), 8.07 (d, j=9.8 hz, 1H), 7.94 (d, j=0.7 hz, 1H), 7.65 (s, 1H), 7.53-7.43 (M, 2H), 7.21 (d, j=9.9 hz, 1H), 3.45-3.35 (M, 4H), 2.89-2.75 (M, 4H), 2.15 (s, 3H), 1.12 (s, 9H) s (ESI): lcm 497.30; actual measurement value [ M+H] + ＝498.30。
Intermediate example 9: preparation of N- (tert-butyl) -3- ((5-methyl-2- ((4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-003)
Method and intermediates referring to scheme 3, step 2The procedure of example 7 was followed, under appropriate conditions as understood in the art, to give the title compound N- (tert-butyl) -3- ((5-methyl-2- ((4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (1.2 g, 72.14% yield) as a white solid using N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide and tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate. 1 H NMR(400MHz,DMSO)δ8.87(s,1H),8.56(s,1H),8.11(s,2H),7.92(s,1H),7.65–7.40(m,5H),7.04(d,J＝8.5Hz,2H),3.17(s,3H),3.00(d,J＝12.0Hz,2H),2.55(dd,J＝12.1,10.3Hz,2H),2.48(d,J＝15.5Hz,3H),2.13(s,3H),1.64(d,J＝11.5Hz,2H),1.46(dd,J＝12.2,3.6Hz,2H),1.12(s,9H).LCMS(ESI):(M+H) + Calculated (M) 495.3, found 495.2.
Intermediate example 10: preparation of N- (tert-butyl) -3- ((5-methyl-2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-004)
Referring to the procedure of scheme 3, step 2 and the procedure of intermediate example 7, the title compound N- (tert-butyl) -3- ((5-methyl-2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (1.5 g, yield 90.15%) was prepared as a white solid using N- (tert-butyl) -3- ((2-chloro-5-methylpyrimidin-4-yl) amino) benzenesulfonamide and tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate under appropriate conditions as understood in the art. 1 H NMR(400MHz,DMSO)δ8.70(s,1H),8.51(s,1H),8.14(s,2H),7.89(s,1H),7.57(s,1H),7.48(d,J＝6.3Hz,4H),6.80(d,J＝8.9Hz,2H),3.57(s,2H),3.17(s,1H),3.00–2.89(m,4H),2.81(dd,J＝10.1,5.8Hz,5H),2.12(s,3H),1.12(s,9H).LCMS(ESI):(M+H) + Calculated (M) 496.3, found 496.2.
Intermediate example 11: preparation of 6- (4- (tert-Butoxycarbonyl) piperazin-1-yl) pyridazine-3-carboxylic acid
Reference scheme 4 preparation of 6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridazin-3-carboxylic acid.
Step 1, methyl 6-chloropyridazine-3-carboxylate (500.00 mg,2.897 mmol) and tert-butyl piperazine-1-carboxylate (809.45 mg, 4.348 mmol) were dissolved in DMF (10.00 mL), DIEA (1.437 mL,8.692 mmol) was added, and the reaction mixture was reacted at 60℃for 12h. LC-MS detected completion of the reaction. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic phase is separated, washed with saturated salt water and concentrated to obtain crude product. The crude product was purified by column chromatography (eluent (v/v): PE/ea=5/1, v/v) to give methyl 6- (4- (tert-butoxycarbonyl) piperazin-1-yl) pyridazine-3-carboxylate (900 mg, yield 75.16%) as a white solid. LCMS (ESI): c (C) 15 H 23 N 4 O 4 + [M+H] + Calculated 323.16, measured 323.20.
Step 2, methyl 6- (4- (t-Butoxycarbonyl) piperazin-1-yl) pyridazine-3-carboxylate (400 mg,1.241 mmol) was dissolved in a mixed solvent of 1, 4-dioxane and water (1/1; 10 mL), lithium hydroxide (260.32 mg,6.204 mmol) was added, and the reaction mixture was then reacted at 60℃for 12 hours. LC-MS detected completion of the reaction. The organic phase was removed by rotary evaporation of the reaction mixture under reduced pressure, and the remaining aqueous phase was adjusted to ph=6 with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phase was separated and concentrated under reduced pressure to give 6- (4- (t-butoxycarbonyl) piperazin-1-yl) pyridazin-3-carboxylic acid (300 mg, yield 76.06%) as a white solid which was used in the next step without purification. LCMS (ESI): c (C) 14 H 21 N 4 O 4 + [M+H] + Calculated 309.15, measured 309.20.
Intermediate example 12: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (piperazin-1-yl) pyridazine-3-carboxamide
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (piperazin-1-yl) pyridazine-3-carboxamide was prepared according to the method of scheme 5.
6- (4- (t-Butoxycarbonyl) piperazin-1-yl) pyridazine-3-carboxylic acid (300 mg,1.135 mmol) prepared in intermediate example 11 and 4- (((1 r,4 r) -4-aminocyclohexyl) oxy) -2-chlorobenzonitrile (326.61 mg,1.135 mmol) were dissolved in DMF (5.00 mL), HATU (647.40 mg,1.703 mmol) and DIEA (0.938 mL,5.676 mmol) were added and the resulting reaction mixture was reacted at room temperature for 30 min. LC-MS detected completion of the reaction. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic phase is separated, saturated brine is washed, and the crude product is obtained after concentration. The crude product was purified by column chromatography (eluent (v/v): DCM/meoh=100/1) to give tert-butyl 4- (6- (((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) carbamoyl) pyridazin-3-yl) piperazine-1-carboxylate (250 mg, yield 39.49%) as a white solid. LCMS (ESI): c (C) 27 H 34 ClN 6 O 4 + [M+H] + Calculated 541.23, measured 541.30.
Tert-butyl 4- (6- (((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) carbamoyl) pyridazin-3-yl) piperazine-1-carboxylate (250 mg, 0.460 mmol) was dissolved in a mixed solvent of DMF (5.00 mL) and TFA (1.00 mL), and the reaction mixture was then reacted at room temperature for 3h. LC-MS detected completion of the reaction. The organic phase was removed by rotary evaporation of the reaction mixture under reduced pressure, and the remaining aqueous phase was purified with saturated NaHCO 3 The solution was adjusted to ph=8 and then extracted with ethyl acetate. The organic phase was separated and concentrated under reduced pressure to give N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (piperazin-1-yl) pyridazine-3-carboxamide as a white solid (170 mg, yield 75.10%) which was used in the next step without purification. LCMS (ESI): c (C) 22 H 26 ClN 6 O 2 + [M+H] + Calculated 441.17, measured 441.20.
Intermediate example 13: preparation of 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234)
Referring to the procedure of scheme 7, 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione is prepared.
The starting material methyl 2, 5-dimethylbenzoate (3.4 g,20.6 mmol) was dissolved in 100mL of carbon tetrachloride, and N-bromosuccinimide (8.0 g,45 mmol) and dibenzoyl peroxide (0.31 g,1.26 mmol) were added sequentially. The reaction mixture was refluxed at 80℃for 12h, cooled to room temperature, diluted with 100mL of petroleum ether, washed twice with water and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent (v/v): EA/pe=0/1-1/20) to give methyl 2, 5-bis (bromomethyl) benzoate as an intermediate compound (white solid, 5.0g, yield: 76%).
Cesium carbonate (1.6 g,5 mmol) was added to a mixed solvent of 50mL of 1, 2-dichloroethane and 5mL of hexafluoroisopropanol, stirred at 65℃for 15min, and 3-amino-2, 6-piperidinedione hydrochloride (8.21 g,5 mmol) and methyl 2, 5-bis (bromomethyl) benzoate (1.6 g,5 mmol) were added in sequence, and stirred at 65℃for 12h. After the reaction was completed, the reaction mixture was cooled to room temperature and washed with water. The organic phase was separated, the solvent was removed by distillation under the reduced pressure, and the residue was separated by column chromatography over silica gel (eluent (v/v): meOH/dcm=0/1-1/10). The obtained product was further purified by beating with acetonitrile to obtain a white powder (455 mg, yield: 27%). 1 HNMR(500MHz,DMSO-d 6 ) δ11.00 (s, 1H), 7.78-7.66 (m, 2H), 7.59 (dd, j=7.9, 1.5hz, 1H), 5.11 (dd, j=13.3, 5.1hz, 1H), 4.83 (s, 2H), 4.47 (d, j=17.3 hz, 1H), 4.34 (d, j=17.4 hz, 1H), 2.91 (ddd, j=17.3, 13.6,5.4hz, 1H), 2.68-2.55 (m, 1H), 2.39 (qd, j=13.3, 4.5hz, 1H), 2.01 (dtd, j=12.7, 5.3,4.7,1.9hz, 1H) LCMS (ESI) m/z calculated as C 14 H 14 BrN 2 O 3 + [M+H] + 337.0; found, 337.3.
Intermediate example 14: preparation of 3- (5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03421)
Referring to the procedure of scheme 9, 3- (5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione is prepared.
At 25 ℃ under the protection of argon, to 3- To a solution of (5-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (10 g,30.945 mmol) in anhydrous dioxane (280 mL) was added (tributylstannyl) methanol (14.90 g,46.418 mmol) and Pd (PPh 3 ) 4 (1.32 g,1.145 mmol). The mixture was heated to 90 ℃ and stirred for 16 hours. TLC detection showed complete consumption of starting material. The mixture was cooled to 25 ℃ and concentrated in vacuo to give the crude product. The crude product was triturated with DCM (200 mL) and filtered to give 3- (5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione as a grey solid (7.5 g,27.34 mmol, yield 88.36%). 1 H NMR (400 mhz, dmso) δ10.98 (s, 1H), 7.74-7.64 (m, 1H), 7.55 (s, 1H), 7.45 (d, j=7.8 hz, 1H), 5.40 (t, j=5.7 hz, 1H), 5.11 (dd, j=13.3, 5.1hz, 1H), 4.62 (d, j=5.7 hz, 2H), 4.38 (dd, j=53.1, 17.2hz, 2H), 3.03 (2.82) m, 1H), 2.60 (d, j=17.5 hz, 1H), 2.39 (dd, j=13.1, 4.4hz, 1H), 2.08-1.92 (m, 1H). LCMS (ESI): calculated values: [ M+H ]]++ = 275.10; actual measurement value [ M+H] + ＝275.0。
Intermediate example 15: preparation of 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445)
Referring to the method of scheme 9, 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione is prepared.
To a solution of 3- (5-bromo-4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (2.0 g,5.863 mmol) in anhydrous dioxane (56 mL) was added (tributylstannyl) methanol (2.82 g,8.794 mmol) and Pd (PPh) at 25 ℃ 3 ) 4 (0.34 g,0.293 mmol). The mixture was degassed 3 times and backfilled with N 2 . The mixture was heated to 90 ℃ and stirred for 16 hours. TLC (DCM/meoh=10:1) and LCMS showed complete consumption of starting material. The mixture was cooled to room temperature and filtered to remove black solids. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluent (v/v): DCM/meoh=1/0-10/1) to give 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (410 mg,1.403mmol,yield 23.93%). 1 H NMR (400 MHz, DMSO). Delta.10.99 (s, 1H), 7.80-7.42 (M, 2H), 5.46 (t, J=5.7 Hz, 1H), 5.11 (dd, J=13.3, 5.0Hz, 1H), 4.65 (d, J=5.6 Hz, 2H), 4.46 (dd, J=69.4, 17.3Hz, 2H), 3.03-2.81 (M, 1H), 2.60 (d, J=17.6 Hz, 1H), 2.46-2.31 (M, 1H), 2.09-1.93 (M, 1H) S (ESI) calculated: [ M+H] + = 293.09; actual measurement value [ M+H] + ＝293.10.
Intermediate example 16: preparation of 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446)
Referring to the method of scheme 9, 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione is prepared.
To a solution of 3- (5-bromo-7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (2.0 g,5.863 mmol) in anhydrous dioxane (56 mL) was added (tributylstannyl) methanol (2.82 g,8.794 mmol) and Pd (PPh) at 25 ℃ 3 ) 4 (0.34 g,0.293 mmol) (56 mL). The mixture was degassed 3 times and backfilled with N 2 . The mixture was heated to 90 ℃ and stirred for 16 hours. TLC (DCM/meoh=10:1) showed complete consumption of starting material. The mixture was cooled to room temperature and filtered to remove black solids. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was triturated with DCM (30 mL) and filtered to give 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione as a grey solid (1.01 g,3.456mmol, yield 58.94%). 1 H NMR (400 mhz, dmso) δ10.99 (s, 1H), 7.38 (s, 1H), 7.20 (d, j=10.6 hz, 1H), 5.50 (t, j=5.7 hz, 1H), 5.08 (dd, j=13.3, 5.1hz, 1H), 4.62 (d, j=5.7 hz, 2H), 4.40 (dd, j=54.3, 17.6hz, 2H), 2.99-2.82 (M, 1H), 2.60 (d, j=17.5 hz, 1H), 2.38 (dd, j=13.1, 4.4hz, 1H), 2.11-1.93 (M, 1H) ·lcms (ESI) ·calculated values: [ m+h] + = 293.09; actual measurement value [ M+H ] + ＝293.0.
Intermediate example 17: preparation of 3- (4-bromo-6- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03419)
Referring to scheme 10, 3- (4-bromo-6- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03419) was prepared.
Step 1:
the starting material methyl 2, 5-dimethyl-3-bromobenzoate (5.0 g,20.6 mmol) was dissolved in 100mL carbon tetrachloride, and N-bromosuccinimide (8.0 g,45 mmol) and dibenzoyl peroxide (0.31 g,1.26 mmol) were added sequentially. The reaction mixture was refluxed at 80 ℃ for 12h, cooled to room temperature, and diluted with 100mL petroleum ether. The resulting mixture was diluted with water twice and washed once with saturated brine. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under the reduced pressure from the filtrate. The residue was separated by silica gel column chromatography (PE/ea=1/0-20/1) to give the intermediate compound (6.3 g, yield: 76%) as a white solid.
Step 2:
cesium carbonate (16.25 g,49.89 mmol) was added to a mixed solvent of 500mL of 1, 2-dichloroethane and 50mL of hexafluoroisopropanol, and the resulting mixture was stirred at 65℃for 15min, followed by the sequential addition of 3-amino-2, 6-piperidinedione hydrochloride (8.21 g,49.89 mmol) and compound 363126 (20 g,49.89 mmol) obtained in step 1. The reaction mixture was stirred at 65℃for 12h. The reaction mixture was filtered while it was still hot to remove insoluble matters, and the filtrate was washed with saturated brine and then the organic solvent was distilled off under reduced pressure. The remaining solid was slurried with 50mL of dichloromethane and 200mL of petroleum ether. The resulting mixture was filtered, and the filtered solid was washed with 50mL of methylene chloride and 50mL of diethyl ether to give the product GT-03419 (11 g, yield: 42%) as a gray powder. 1 H NMR (500 MHz, methanol-d) 4 ) Delta 7.90 (d, j=1.5 hz, 1H), 7.84 (d, j=1.5 hz, 1H), 5.17 (dd, j=13.4, 5.2hz, 1H), 4.68 (s, 2H), 4.45 (q, j=17.6 hz, 2H), 2.91 (ddd, j=17.6, 13.6,5.4hz, 1H), 2.79 (ddd, j=17.6, 4.6,2.4hz, 1H), 2.53 (qd, j=13.4, 4.7hz, 1H), 2.19 (dtd, j=13.0, 5.4,2.4hz, 1H) MS (ESI) m/z calculated value C 14 H 13 Br 2 N 2 O 3 + [M+H] + 414.9; found, 415.1.
Intermediate example 18: preparation of N- (tert-butyl) -3- ((5-methyl-2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-D-89)
Referring to scheme 16, N- (tert-butyl) -3- ((5-methyl-2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-D-89) (white solid, 1.1 g) was prepared. 1 H NMR (400 mhz, meod) delta 8.07 (s, 1H), 7.80 (d, j=7.9 hz, 1H), 7.78-7.69 (m, 2H), 7.58 (t, j=8.0 hz, 1H), 7.34 (d, j=9.0 hz, 2H), 7.16 (d, j=9.0 hz, 2H), 3.83 (d, j=12.9 hz, 2H), 3.33 (d, j=11.0 hz, 1H), 3.10 (t, j=12.1 hz, 2H), 2.76 (s, 3H), 2.33-2.17 (m, 5H), 1.88 (qd, j=12.5, 3.8hz, 2H), 1.16 (d, j=5.5 hz, 9H). LCMS (ESI): calculated values, 524.3; found, 524.4.
Intermediate example 19: preparation of N- (tert-butyl) -3- ((5-methyl-2- ((4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-D-90)
Referring to scheme 16, N- (tert-butyl) -3- ((5-methyl-2- ((4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-D-90) was prepared (white solid, 0.90 g). 1 H NMR (400 mhz, meod) delta 8.07 (s, 1H), 7.82 (d, j=7.9 hz, 1H), 7.75 (s, 1H), 7.70 (d, j=8.3 hz, 1H), 7.60 (t, j=7.9 hz, 1H), 7.43 (d, j=8.9 hz, 2H), 7.28 (d, j=9.0 hz, 2H), 3.98 (s, 1H), 3.84 (d, j=12.7 hz, 2H), 3.59-3.47 (m, 4H), 3.40 (s, 4H), 3.25 (d, j=11.6 hz, 2H), 2.34-2.20 (m, 5H), 2.15-1.98 (m, 2H), 1.18 (d, j=15.hz, 9H). LCMS (ESI): calculated value, 579.3; found 579.4.
Intermediate example 20: 5-chloro-N 2 - (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N 4 Preparation of- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-86)
Referring to scheme 16, 5-chloro-N is prepared 2 - (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-86) (brown solid, 2.46 g). 1 H NMR (400 mhz, dmso) δ9.51 (s, 1H), 9.14 (s, 2H), 8.43 (d, j=8.3 hz, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.85 (dd, j=7.9, 1.2hz, 1H), 7.63 (t, j=7.7 hz, 1H), 7.51 (s, 1H), 7.37 (t, j=7.5 hz, 1H), 6.70 (s, 1H), 4.56 (dd, j=12.0, 6.0hz, 1H), 3.23 (s, 4H), 3.04 (d, j=4.3 hz, 4H), 2.09 (s, 3H), 1.19 (dd, j=24.2, 6.4hz, 12H). S (ESI): calculated value, 559.2; found, 559.1.
Intermediate example 21: 5-chloro-N 2 - (2-isopropoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) -N 4 Preparation of- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-87)
Referring to scheme 16, 5-chloro-N is prepared 2 - (2-isopropoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-87) (white solid, 1.2 g). 1 H NMR (400 mhz, dmso) δ9.93 (s, 1H), 9.19 (s, 2H), 8.93 (s, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.73 (t, j=7.7 hz, 1H), 7.51 (t, j=7.7 hz, 1H), 7.39 (s, 1H), 6.81 (s, 1H), 4.71-4.36 (m, 1H), 3.48 (dt, j=13.4, 6.7hz, 1H), 2.57 (t, j=5.3 hz, 3H), 2.13 (s, 2H), 2.04 (s, 3H), 1.82 (s, 2H), 1.24 (d, j=6.0 hz, 6H), 1.14 (d, j=6.8 hz, 6H) s (ESI) calculated values of s (587.3; found, 587.3.
Intermediate example 22: 5-chloro-N 2 - (2-isopropoxy-5-methyl-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -N 4 Preparation of- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-88)
Referring to scheme 16, 5-chloro-N is prepared 2 - (2-isopropoxy-5-methyl-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-88) (brown solid, 1.2 g). 1 H NMR (400 mhz, dmso) δ9.47 (s, 1H), 8.46 (d, j=7.9 hz, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.83 (d, j=7.9 hz, 1H), 7.61 (t, j=7.8 hz, 1H), 7.49 (s, 1H), 7.35 (t, j=7.7 hz, 1H), 6.70 (s, 1H), 4.60-4.42 (m, 1H), 3.54-3.36 (m, 8H), 3.26-3.06 (m, 4H), 2.66 (t, j=11.1 hz, 2H), 2.15 (d, j=11.0 hz, 1H), 2.09 (s, 3H), 1.79 (s, 2H), 1.26 (dds, 1H), 1.60-4.42 (m, 1H), 3.54-3.36 (m, 8H), 2.26-3.06 (m, 4H); found, 642.3.
Intermediate example 23: preparation of (2- ((5-chloro-2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino oxide (GT-D-39)
Referring to scheme 16, (2- ((5-chloro-2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (GT-D-39) (yellow solid, 7.9 g) was prepared. 1 H NMR (400 mhz, dmso) delta 11.57 (s, 1H), 9.55 (s, 1H), 9.17 (s, 2H), 8.76 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.59 (dd, j=13.3, 7.7hz, 1H), 7.50-7.30 (m, 2H), 7.17 (t, j=7.3 hz, 1H), 6.73 (d, j=2.1 hz, 1H), 6.56 (dd, j=8.6, 2.2hz, 1H), 3.79 (s, 3H), 3.49-3.36 (m, 4H), 3.26 (m, 4H), 1.80 (s, 3H), 1.77 (s, 3H). LCMS (ESI) calculated values, 487.2; found, 487.2.
Intermediate example 24: preparation of (R) -N- (5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) -4- (piperazin-1-yl) benzamide (GT-M-08)
Referring to scheme 17, (R) -N- (5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3, 4-c)]Pyrazol-3-yl) -4- (piperazin-1-yl) benzamide (GT-M-08) (white solid, 0.165 g). 1 H NMR (400 mhz, dmso) δ10.71 (s, 1H), 7.89 (dd, j=9.0, 2.7hz, 2H), 7.59-7.20 (m, 5H), 6.97 (dd, j=9.0, 1.9hz, 2H), 5.11 (d, j=12.1 hz, 1H), 4.79 (dd, j=23.9, 12.6hz, 1H), 4.62-4.26 (m, 4H), 3.34 (d, j=2.4 hz, 4H), 3.23-3.09 (m, 4H), 2.93-2.67 (m, 4H). LCMS (ESI) calculated values of 461.2; found, 461.6.
Intermediate example 25: preparation of 2- ((2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-10)
Referring to scheme 16, 2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-10) (white solid, 1.87 g) was prepared. 1 H NMR (400 mhz, meod) delta 8.01 (s, 1H), 7.73 (d, j=7.9 hz, 1H), 7.59 (d, j=3.8 hz, 2H), 7.36 (dt, j=8.4, 4.1hz, 1H), 7.18 (d, j=8.6 hz, 1H), 6.79 (d, j=2.1 hz, 1H), 6.68 (dd, j=8.7, 2.2hz, 1H), 6.48 (s, 1H), 3.87 (s, 3H), 3.66 (s, 4H), 3.56-3.48 (m, 4H), 3.43-3.37 (m, 4H), 2.91 (d, j=13.7 hz, 3H) s (ESI): calculated value, 501.2; actual measurement, 501.2.
Intermediate example 26: preparation of 2- ((2- ((4- (4-aminopiperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-11)
Referring to scheme 16, 2- ((2- ((4- (4-aminopiperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-11) was prepared (brown solid, 0.4 g). 1 H NMR(400MHz,DMSO)δ10.13(s,1H),8.63(d,J＝4.2Hz,1H),8.27(s,1H),8.14(s,1H),7.74–7.60(m,1H),7.44(dd,J＝6.3,1.3Hz,2H),7.36(d,J＝8.7Hz,1H),7.08–7.00(m,1H),6.57(d,J＝2.5Hz,1H),6.51(s,1H),6.43(dd,J＝8.8,2.5Hz,1H),3.77(s,3H),3.57(d,J＝12.6Hz,3H),2.75(d,J＝3.7Hz,4H).LCMS (ESI) calculated, 515.2; found, 515.2.
Intermediate example 27: preparation of 2- ((2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-12)
Referring to scheme 16, 2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-12) was prepared (purple solid, 0.34 g). 1 H NMR (400 mhz, dmso) δ10.60 (s, 1H), 10.10 (s, 1H), 9.99 (s, 1H), 9.75 (s, 1H), 8.82 (d, j=4.6 hz, 1H), 8.14 (s, 1H), 7.77 (d, j=7.7 hz, 1H), 7.57 (d, j=3.2 hz, 2H), 7.33-7.26 (m, 1H), 7.19 (s, 1H), 6.81 (s, 1H), 6.68 (s, 1H), 6.54 (s, 1H), 3.78 (d, j=26.5 hz, 15H), 3.53 (s, 9H), 2.84 (s, 2H), 2.76 (d, j=4.5 hz, 3H), 2.22 (d, j=10.6 hz, 2H), 1.87 (d, j=9.5 hz, 1.23, 2H), and (s, 1.23, 2H); found, 584.0.
Intermediate example 28: preparation of 2- ((2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) piperidin-4-yl) amino) -N-methylbenzamide (GT-M-171)
Referring to scheme 16, 2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) piperidin-4-yl) amino) -N-methylbenzamide (GT-M-171) was prepared (yellow solid, 20.5 g). 1 H NMR (400 mhz, dmso) δ10.39 (s, 1H), 9.20 (s, 1H), 8.80 (s, 2H), 8.69 (d, j=4.6 hz, 1H), 8.13 (s, 1H), 7.73 (d, j=7.7 hz, 1H), 7.53 (s, 2H), 7.35 (d, j=8.6 hz, 1H), 7.20 (s, 1H), 6.70 (d, j=2.2 hz, 1H), 6.59-6.49 (m, 2H), 3.80 (s, 3H), 3.36 (d, j=5.2 hz, 4H), 3.25 (s, 4H), 2.76 (lcm, j=4.5 hz, 3H). S (ESI). Calculated values, 501.2; actual measurement, 501.3.
Intermediate example 29: preparation of 2- ((2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-172)
Referring to scheme 16, 2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-172) was prepared (white solid, 1.8 g). 1 H NMR (400 mhz, dmso) delta 10.60 (s, 1H), 9.98 (s, 1H), 9.38 (s, 2H), 8.83 (d, j=4.5 hz, 1H), 8.17 (s, 1H), 7.78 (d, j=7.8 hz, 1H), 7.57 (d, j=3.9 hz, 2H), 7.34-7.15 (m, 2H), 6.87 (d, j=54.9 hz, 2H), 6.59 (s, 1H), 3.82 (s, 5H), 3.21 (s, 1H), 2.98 (s, 2H), 2.69 (t, j=41.5 hz, 4H), 2.54 (t, j=5.3 hz, 3H), 2.17 (s, 2H), 1.84 (s, 2H): calculated as s (ESI 529.3; found, 529.3.
Intermediate example 30: preparation of N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-151)
Referring to scheme 19, N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-151) (white solid, 1.7 g) was prepared. 1 H NMR (400 mhz, meod) delta 8.60 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 7.41 (d, j=8.3 hz, 2H), 7.20 (d, j=8.6 hz, 2H), 5.13 (s, 2H), 3.59 (d, j=4.7 hz, 4H), 3.49 (s, 4H), 3.20 (d, j=16.1 hz, 3H), 3.13 (s, 3H) LCMS (ESI) calculated, 538.20; found, 538.3.
Intermediate example 31: preparation of N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-152)
Referring to scheme 19, N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-152) (brown solid, 1.2 g) was prepared. 1 H NMR (400 mhz, dmso) delta 10.92 (s, 1H), 9.52 (s, 2H), 9.06 (s, 1H), 8.48 (s, 1H), 7.43-7.25 (m, 6H), 7.18 (s, 1H), 6.97 (d, j=8.3 hz, 2H), 4.64 (d, j=5.2 hz, 2H), 3.37 (s, 4H), 3.20 (s, 4H), 3.15 (s, 3H), 2.87 (s, 3H). LCMS (ESI) calculated values, 536.2; found 536.7.
Intermediate example 32: preparation of N-methyl-N- (3- (((2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-153)
Referring to scheme 19, N-methyl-N- (3- (((2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-153) (white solid, 1.069 g) was prepared. 1 H NMR (400 mhz, meod) delta 8.36 (d, j=22.7 hz, 1H), 7.77 (t, j=8.4 hz, 2H), 7.55 (d, j=8.5 hz, 2H), 7.47 (t, j=7.9 hz, 1H), 7.35 (d, j=7.8 hz, 1H), 7.26 (s, 2H), 7.14 (s, 1H), 4.75 (s, 2H), 3.82 (dd, j=24.4, 12.5hz, 4H), 3.63 (d, j=11.4 hz, 1H), 3.27 (d, j=8.0 hz, 3H), 2.89 (d, j=18.3 hz, 3H), 2.81 (s, 3H), 2.50 (d, j=13.0 hz, 2H), 2.37 (d, j=10.7 hz, 2H) s (ESI) calculated s (564.2). Found, 564.1.
Intermediate example 33: preparation of N-methyl-N- (3- (((2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-174)
Referring to scheme 19, N-methyl-N- (3- (((2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonate was prepared Amide (GT-M-174) (white solid, 707 mg). 1 HNMR (400 mhz, meod) δ8.58 (dd, j=17.7, 2.3hz, 2H), 8.39 (s, 1H), 7.76 (dd, j=44.2, 9.0hz, 4H), 5.16 (s, 2H), 3.83 (d, j=13.7 hz, 4H), 3.27 (s, 3H), 3.16 (s, 3H), 2.80 (s, 3H), 2.55-2.33 (m, 4H). LCMS (ESI) calculated values, 566.2; found, 566.3.
Intermediate example 34: preparation of N-methyl-N- (3- (((2- ((4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-175)
Referring to scheme 19, N-methyl-N- (3- (((2- ((4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-175) was prepared (brown solid, 560 mg). 1 HNMR (400 mhz, meod) δ8.58 (dd, j=18.6, 2.4hz, 1H), 8.37 (s, 1H), 7.66 (s, 2H), 5.15 (s, 1H), 4.00-3.60 (m, 6H), 3.26 (s, 2H), 3.16 (s, 2H), 2.54 (dd, j=43.4, 11.6hz, 2H). LCMS (ESI) calculated values, 621.3; found, 621.4.
Intermediate example 35: n (N) 4 - (3- (methylsulfonyl) benzyl) -N 2 Preparation of- (4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (GT-M-191)
Referring to scheme 19, N is prepared 4 - (3- (methylsulfonyl) benzyl) -N 2 - (4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (GT-M-191) (purple solid, 500 mg). 1 H NMR (400 mhz, dmso) δ9.78 (s, 1H), 8.62 (s, 3H), 8.26 (s, 1H), 7.90 (s, 1H), 7.81 (d, j=7.1 hz, 1H), 7.61 (t, j=7.6 hz, 2H), 7.31 (d, j=7.9 hz, 2H), 6.91 (d, j=8.7 hz, 2H), 4.71 (d, j=5.5 hz, 2H), 3.35-3.20 (m, 8H), 3.16 (d, j=11.3 hz, 3H). LCMS (ESI) calculated values, 507.2; found, 507.4.
Intermediate example 36: preparation of N-methyl-N- (3- (((2- ((4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-193)
Referring to scheme 20, N-methyl-N- (3- (((2- ((4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-193) (white solid, 0.87 g) was prepared. 1 H NMR (400 mhz, dmso) delta 9.75 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.51 (d, j=8.0 hz, 2H), 7.41-7.31 (m, 2H), 7.24 (dd, j=16.3, 7.7hz, 2H), 7.09 (d, j=8.4 hz, 2H), 4.66 (d, j=5.6 hz, 2H), 3.37 (d, j=12.2 hz, 2H), 3.15 (s, 3H), 3.00 (q, j=11.9 hz, 2H), 2.86 (s, 3H), 2.77 (t, j=12.0 hz, 1H), 1.92 (d, j=13.5 hz, 2H), 1.73 (dd, j=22.9, 12.5hz, 2H). Actual measurement 535.3.
Intermediate example 37: preparation of 4- (((4- (5-chloro-2- (piperidin-4-ylamino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-158)
Referring to scheme 22, 4- (((4- (5-chloro-2- (piperidin-4-ylamino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-158) was prepared (yellow solid, 900 mg). 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.34(s,1H),8.12(t,J＝6.2Hz,1H),8.02(s,1H),7.39(s,1H),7.11(s,1H),6.99(s,1H),3.92(s,2H),3.68(d,J＝6.1Hz,2H),3.49(t,J＝11.3Hz,3H),3.31(d,J＝12.7Hz,2H),3.03(d,J＝10.3Hz,2H),2.07(d,J＝10.8Hz,2H),1.88(d,J＝13.4Hz,2H),1.77–1.59(m,4H).LCMS(ESI):C 20 H 25 ClN 6 OS + ；[M+H] + Calculated 433.16; actual measurement value: 433.1.
intermediate example 38: preparation of 4- (((5 ' -chloro-2 ' - (piperidin-4-ylamino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-159)
Referring to scheme 21, 4- (((5 ' -chloro-2 ' - (piperidin-4-ylamino) - [2,4' -bipyridine) is prepared]-6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-159) (yellow solid, 1.5g, 86.9% yield). 1 H NMR (400 mhz, dmso) delta 8.55 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.57-7.43 (m, 1H), 7.10 (t, j=6.4 hz, 1H), 6.95 (d, j=7.3 hz, 1H), 6.76 (d, j=7.2 hz, 1H), 6.67 (d, j=10.0 hz, 2H), 4.08-3.80 (m, 3H), 3.66 (d, j=6.4 hz, 2H), 3.46 (dd, j=11.9, 10.5hz, 2H), 3.29 (s, 2H), 3.04 (dd, j=18.8, 7.9hz, 2H), 2.07 (d, j=10.8 hz, 2H), 1.84 (d, j=13.2 hz, 2H), 1.73-1.46 (d, j=6.4 hz, 2H) s (i. 427.2 s); found, 427.2.
Intermediate example 39: preparation of 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (4- (piperazin-1-yl) phenyl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-012)
Referring to scheme 23, 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (4- (piperazin-1-yl) phenyl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-012) was prepared (yellow solid, 110 mg). 1 H NMR (400 mhz, dmso) delta 10.20-8.61 (m, 1H), 7.87 (d, j=8.5 hz, 2H), 7.63 (dd, j=11.3, 8.4hz, 4H), 7.49 (d, j=3.5 hz, 1H), 7.27 (d, j=3.6 hz, 1H), 7.12 (td, j=8.6, 3.1hz, 1H), 7.07 (d, j=8.8 hz, 2H), 6.92 (dd, j=8.9, 4.8hz, 1H), 6.87 (dd, j=9.2, 3.0hz, 1H), 6.33 (s, 1H), 4.64 (d, j=17.5 hz, 1H), 4.02 (d, j=17.5 hz, 1H), 3.29 (d, j=4.4 hz, 5H), 3.12-3.00 (m, 4.8hz, 1H), 6.38 (s, 1H), 6.87 (dd, j=9.0 hz, 1H); found, 544.2.
Intermediate example 40: preparation of 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (6- (piperazin-1-yl) pyridazin-3-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-014)
Referring to scheme 24, 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (6- (piperazin-1-yl) pyridazin-3-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-014) was prepared (brown solid, 130 mg). 1 H NMR (400 mhz, dmso) δ8.31 (d, j=8.3 hz, 2H), 8.06 (d, j=9.6 hz, 1H), 7.68 (d, j=7.9 hz, 1H), 7.48 (d, j=3.6 hz, 1H), 7.33 (d, j=9.7 hz, 1H), 7.25 (d, j=3.5 hz, 1H), 7.11 (td, j=8.6, 3.1hz, 1H), 6.94-6.84 (m, 2H), 6.33 (s, 1H), 4.69 (d, j=17.8 hz, 1H), 4.07 (d, j=17.8 hz, 1H), 3.66-3.54 (m, 4H), 3.17 (s, 1H), 2.91-2.78 (m, 4H), 1.23 (s, 1H) [ LCMS (546.2; found, 546.2.
Intermediate example 41: preparation of 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (piperazin-1-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-69)
Referring to scheme 25, 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (piperazin-1-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-69) was prepared (yellow solid, 515 mg). 1 H NMR (400 mhz, dmso) delta 7.48 (d, j=3.5 hz, 1H), 7.39 (d, j=8.4 hz, 1H), 7.24 (dd, j=11.9, 2.8hz, 2H), 7.15 (d, j=1.8 hz, 1H), 7.13-7.05 (m, 1H), 6.90 (dd, j=8.9, 4.8hz, 1H), 6.82 (dd, j=9.2, 2.9hz, 1H), 6.29 (s, 1H), 4.50 (d, j=17.0 hz, 1H), 3.89 (d, j=17.0 hz, 2H), 3.13 (s, 5H), 2.91 (s, 5H), 1.24 (s, 1H). LCMS (ESI): calculated values, 468.2; found, 468.2.
Intermediate example 42: preparation of 2- (5-fluoro-2-hydroxyphenyl) -2- (6- (4- (methylamino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-70)
Referring to scheme 25, 2- (5-fluoro-2-hydroxyphenyl) -2- (6- (4- (methyl) is preparedAmino) piperidin-1-yl) -1-oxoisoindolin-2-yl-N- (thiazol-2-yl) acetamide (GT-D-70) (brown solid, 186 mg). 1 H NMR (400 mhz, dmso) delta 7.40 (dd, j=29.5, 5.8hz, 2H), 7.22 (d, j=7.5 hz, 1H), 7.16 (d, j=19.7 hz, 3H), 7.05 (d, j=6.2 hz, 1H), 6.91-6.76 (m, 2H), 6.24 (s, 1H), 4.54 (d, j=17.0 hz, 1H), 3.94 (d, j=17.0 hz, 1H), 3.67 (d, j=12.1 hz, 2H), 3.17 (s, 1H), 2.78 (t, j=11.3 hz, 2H), 2.31 (d, j=5.8 hz, 3H), 1.89 (d, j=11.2 hz, 2H), 1.35 (d, j=11.1 hz, 2H) s (ESI) calculated values of s (496.2; found, 496.2.
Intermediate example 43: preparation of 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (4- (piperazin-1-yl) piperidin-1-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-71)
Referring to scheme 25, 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (4- (piperazin-1-yl) piperidin-1-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-71) was prepared (brown solid, 110 mg). 1 H NMR (400 mhz, dmso) delta 7.45 (s, 1H), 7.36 (d, j=8.4 hz, 1H), 7.22 (d, j=9.5 hz, 4H), 7.07 (s, 1H), 6.91-6.77 (m, 3H), 6.25 (s, 1H), 4.51 (d, j=17.1 hz, 1H), 3.91 (d, j=16.9 hz, 1H), 3.77 (d, j=12.1 hz, 3H), 3.17 (s, 2H), 2.72 (s, 5H), 2.44 (s, 5H), 1.82 (d, j=10.7 hz, 2H), 1.51 (d, j=11.4 hz, 3H), 1.25 (s, 1H) s (ESI) calculated values, 551.2; found, 551.2.
Intermediate example 44: preparation of 9-ethyl-6, 6-dimethyl-11-oxo-8- (piperazin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-D-42)
Referring to scheme 27, 9-ethyl-6, 6-dimethyl-11-oxo-8- (piperazin-1-yl) -6, 11-dihydro-5H-benzo [ b ]]Carbazole-3-carbonitrile (GT-D-42) (white solid, 240 mg). 1 H NMR(400MHz,DMSO)δ13.03(s,1H),9.39(s,2H),8.32(d,J＝8.1Hz,1H),8.05(d,J＝29.2Hz,2H),7.61(d,J＝9.0Hz,1H) 7.38 (s, 1H), 3.24 (d, j=14.9 hz, 8H), 2.73 (d, j=7.5 hz, 2H), 1.79 (s, 6H), 1.29 (t, j=7.5 hz, 3H). LCMS (ESI) calculated, 399.2; found, 399.2.
Intermediate example 45: preparation of 9-ethyl-6, 6-dimethyl-11-oxo-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-D-113)
Referring to scheme 27, 9-ethyl-6, 6-dimethyl-11-oxo-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] is prepared]Carbazole-3-carbonitrile (GT-D-113) (off-white solid, 1.4 g). 1 H NMR (400 mhz, meod) delta 8.39 (d, j=8.2 hz, 1H), 8.23 (s, 1H), 7.86 (s, 1H), 7.62-7.48 (m, 2H), 3.75 (s, 9H), 3.53 (d, j=12.0 hz, 2H), 3.18 (t, j=11.7 hz, 2H), 2.86 (q, j=7.4 hz, 2H), 2.43 (d, j=11.4 hz, 2H), 2.22 (dd, j=20.7, 11.9hz, 2H), 1.82 (s, 6H), 1.37 (t, j=7.5 hz, 3H). LCMS (ESI) calculated values, 482.3; found 482.2.
Intermediate example 46: preparation of 9-ethyl-6, 6-dimethyl-8- (4- (methylamino) piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-D-85)
Referring to scheme 27, 9-ethyl-6, 6-dimethyl-8- (4- (methylamino) piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] is prepared]Carbazole-3-carbonitrile (GT-D-85) (white solid, 130 mg). 1 H NMR (400 mhz, meod) delta 8.31 (d, j=8.2 hz, 1H), 8.11 (s, 1H), 7.77 (s, 1H), 7.45 (d, j=8.2 hz, 1H), 7.36 (s, 1H), 3.29 (d, j=11.9 hz, 2H), 2.91 (t, j=11.7 hz, 2H), 2.78-2.64 (m, 5H), 2.18 (d, j=11.7 hz, 2H), 1.86-1.75 (m, 2H), 1.71 (s, 6H), 1.25 (t, j=7.5 hz, 3H), 1.22-1.18 (m, 1H). S (ESI). Calculated values, 427.3; found, 427.2.
Intermediate example 47: 9-cyclopentyl-N 8 -phenyl-N 2 - (4- (piperazin-1-yl) phenyl) -9H-purine-2, 8-diaminePreparation of (GT-D-62)
Referring to scheme 29, 9-cyclopentyl-N is prepared 8 -phenyl-N 2 - (4- (piperazin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-62) (white solid, 1.18 g). 1 H NMR (400 mhz, meod) delta 8.15 (s, 1H), 7.67-7.52 (m, 4H), 7.46 (dd, j=15.9, 8.0hz, 3H), 7.25 (d, j=9.0 hz, 2H), 3.66 (s, 1H), 3.61-3.53 (m, 4H), 3.47 (dd, j=6.5, 3.6hz, 4H), 2.40 (dd, j=12.8, 7.3hz, 2H), 2.20 (d, j=7.9 hz, 2H), 1.92 (s, 2H), 1.77-1.62 (m, 2H) s (ESI) calculated lcm 455.3; found, 455.0.
Intermediate example 48: 9-cyclopentyl-N 2 - (4- (4- (methylamino) piperidin-1-yl) phenyl) -N 8 Preparation of phenyl-9H-purine-2, 8-diamine (GT-D-67)
Referring to scheme 29, 9-cyclopentyl-N is prepared 2 - (4- (4- (methylamino) piperidin-1-yl) phenyl) -N 8 phenyl-9H-purine-2, 8-diamine (GT-D-67) (yellow solid, 4.6 g). 1 H NMR (400 mhz, meod) delta 8.34 (s, 1H), 7.94-7.82 (m, 4H), 7.57 (dd, j=7.4, 6.3hz, 4H), 7.45 (dd, j=7.7, 4.2hz, 1H), 3.95-3.81 (m, 4H), 3.71-3.60 (m, 2H), 2.89 (s, 1H), 2.81 (s, 3H), 2.51 (t, j=15.4 hz, 4H), 2.43-2.37 (m, 2H), 2.25 (d, j=8.3 hz, 2H), 2.09-2.02 (m, 2H), 1.83-1.71 (m, 2H). LCMS (ESI). Calculated value, 483.3; found 483.3.
Intermediate example 49: 9-cyclopentyl-N 8 -phenyl-N 2 Preparation of- (4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-68)
Referring to scheme 29, 9-cyclopentyl-N is prepared 8 -phenyl group-N 2 - (4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-68) (yellow solid, 4.1 g). 1 H NMR (400 mhz, dmso) delta 7.62 (d, j=8.9 hz, 2H), 7.56 (t, j=3.7 hz, 3H), 7.01-6.94 (m, 2H), 6.80 (d, j=9.0 hz, 2H), 6.42 (t, j=7.1 hz, 1H), 3.53 (d, j=11.9 hz, 2H), 2.67 (s, 4H), 2.54 (d, j=10.1 hz, 2H), 2.42 (s, 2H), 2.38-2.31 (m, 6H), 2.20 (t, j=11.2 hz, 1H), 1.99 (s, 2H), 1.92-1.87 (m, 1H), 1.81 (d, j=10.0 hz, 4H), 1.69-1.61 (m, 2H), 1.52 (dt, j=11.7, 8.7hz, 2H): calculating the value of i. 538.3 hz; found, 538.4.
Intermediate example 50: preparation of 2- (4-phenoxyphenyl) -6- (piperidin-4-yl) nicotinamide (GT-D-66)
Referring to scheme 30, 2- (4-phenoxyphenyl) -6- (piperidin-4-yl) nicotinamide (GT-D-66) (white solid, 1.0 g) was prepared. 1 H NMR (400 mhz, meod) δ8.53 (d, j=8.2 hz, 1H), 7.93 (d, j=8.2 hz, 1H), 7.75 (d, j=8.8 hz, 2H), 7.44 (t, j=8.0 hz, 2H), 7.23 (t, j=7.4 hz, 1H), 7.18-7.04 (m, 4H), 3.60 (d, j=12.7 hz, 2H), 3.52 (t, j=12.0 hz, 1H), 3.24 (t, j=11.8 hz, 2H), 2.31 (d, j=13.5 hz, 2H), 2.26-2.09 (m, 2H) ·lcms (ESI calculated value, 374.2; measured, 374.2.
Intermediate example 51: preparation of 2- (4-phenoxyphenyl) -6- (piperazin-1-yl) nicotinamide (GT-D-76)
Referring to scheme 30, 2- (4-phenoxyphenyl) -6- (piperazin-1-yl) nicotinamide (GT-D-76) is prepared (yellow solid, 436 mg). 1 H NMR (400 mhz, meod) delta 8.14 (d, j=9.2 hz, 1H), 7.69 (d, j=8.7 hz, 2H), 7.47-7.33 (m, 3H), 7.20 (t, j=7.4 hz, 1H), 7.09 (t, j=7.8 hz, 4H), 4.12-4.03 (m, 4H), 3.49-3.43 (m, 5H) LCMS (ESI) calculated values, 375.2; found, 375.2.
Intermediate example 52: preparation of 6- (4- (methylamino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-D-77)
Referring to scheme 30, 6- (4- (methylamino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-D-77) (white solid, 690 m) is prepared. 1 H NMR(400MHz,CDCl 3 ) Delta 7.99 (d, j=8.9 hz, 1H), 7.65 (d, j=8.6 hz, 2H), 7.39 (t, j=7.9 hz, 2H), 7.17 (t, j=7.4 hz, 1H), 7.08 (dd, j=14.0, 8.2hz, 4H), 6.65 (d, j=8.9 hz, 1H), 5.50-5.19 (m, 2H), 4.42 (d, j=13.4 hz, 2H), 3.18-2.90 (m, 2H), 2.78-2.58 (m, 1H), 2.00 (d, j=10.2 hz, 2H), 1.52-1.25 (m, 4H). LCMS (ESI calculated value, 403.2; found, 403.2.
Intermediate example 53: preparation of 2- (4-phenoxyphenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) nicotinamide (GT-D-78)
Referring to scheme 30, 2- (4-phenoxyphenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) nicotinamide (GT-D-78) is prepared (white solid, 355 mg). 1 H NMR(400MHz,CDCl 3 ) Delta 7.89 (d, j=8.8 hz, 1H), 7.55 (d, j=8.7 hz, 2H), 7.30 (t, j=8.0 hz, 2H), 7.09 (d, j=7.4 hz, 1H), 7.04-6.91 (m, 4H), 6.56 (d, j=8.9 hz, 1H), 5.41 (s, 1H), 5.21 (d, j=12.3 hz, 1H), 4.45 (d, j=13.2 hz, 2H), 2.95-2.76 (m, 7H), 2.57 (d, j=4.4 hz, 4H), 2.44 (dd, j=15.1, 7.5hz, 1H), 1.85 (d, j=11.8 hz, 2H), 1.46 (qd, j=12.4, 3.9hz, 2H) s (ESI) calculated values of 458; found 458.2.
Intermediate example 54: preparation of N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (piperazin-1-yl) -1H-pyrazolo [4,3-c ] pyridin-6-amine (GT-D-18)
Referring to scheme 26, N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (piperazin-1-yl) -1H-pyrazolo [4,3-c]Pyridine-6-Amine (GT-D-18) (yellow solid, 0.75 g). 1 H NMR (400 mhz, cdcl 3) delta 8.73 (s, 1H), 8.69 (s, 1H), 8.47 (s, 1H), 8.39 (d, j=5.9 hz, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 6.81 (d, j=5.8 hz, 1H), 4.65 (dt, j=13.3, 6.6hz, 1H), 3.56-3.43 (m, 4H), 3.16-3.00 (m, 4H), 2.90-2.80 (m, 1H), 1.58 (d, j=6.7 hz, 6H), 1.55-1.49 (m, 2H), 1.26-1.19 (m, 2H). LCMS (ESI): calculated, 509.2; found 509.2.
Intermediate example 55: preparation of N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (4-methylamino) piperidin-1-yl) -1H-pyrazolo [4,3-c ] pyridin-6-amine (GT-D-72)
Referring to scheme 26, N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (4-methylamino) piperidin-1-yl) -1H-pyrazolo [4,3-c]Pyridin-6-amine (GT-D-72) (yellow solid, 0.4 g). 1 HNMR (400 mhz, cdcl 3) delta 8.73 (s, 1H), 8.69 (s, 1H), 8.47 (s, 1H), 8.40 (d, j=5.9 hz, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 6.82 (d, j=5.8 hz, 1H), 4.65 (dt, j=13.3, 6.6hz, 1H), 4.09 (t, j=12.3 hz, 2H), 3.05 (t, j=11.3 hz, 2H), 2.85 (ddd, j=12.5, 7.8,4.7hz, 2H), 2.61 (s, 3H), 2.16 (d, j=10.7 hz, 2H), 1.81 (dd, j=20.3, 11.2hz, 2H), 1.58 (d, j=6.7 hz, 6H), 1.54 (dd, j=11.3 hz, 2H), 2.85 (ddd, j=12.7 hz, 2H), 2.61 (ddd, j=3.7 hz, 2H), 2.61 (j=3.7 hz, 2H), 1.38 hz, 3.38 hz, 2H; found, 537.4.
Intermediate example 56: preparation of N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (4- (piperazin-1-yl) piperidin-1-yl) -1H-pyrazolo [4,3-c ] pyridin-6-amine (GT-D-73)
Referring to scheme 26, N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (4- (piperazin-1-yl) piperidin-1-yl) -1H-pyrazolo [4,3-c]Pyridin-6-amine (GT-D-73) (yellow solid, 1.19 g). 1 HNMR(400 mhz, dmso) delta 10.37 (s, 1H), 8.86 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.41 (d, j=5.9 hz, 1H), 8.32 (s, 1H), 7.13 (d, j=5.5 hz, 1H), 4.72 (s, 1H), 4.02 (d, j=12.0 hz, 2H), 3.53 (d, j=57.7 hz, 1H), 3.33-3.27 (m, 2H), 2.88 (t, j=11.6 hz, 2H), 2.76 (s, 4H), 2.35 (d, j=12.0 hz, 1H), 1.87 (d, j=10.4 hz, 2H), 1.60 (d, j=10.0 hz, 2H), 1.47 (d, j=6.6 hz, 6H), 1.36 (d, 2H), 2.28 (t, j=11.6 hz, 2H), 2.35 (d, j=12.0 hz, 1H), 1.47 (v, 1H); found, 592.4.
Intermediate example 57: preparation of 1-isopropyl-N- (2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) -3- (4- (methylamino) piperidin-1-yl) -1H-pyrazolo [4,3-c ] pyridin-6-amine (GT-D-74)
Referring to scheme 26, 1-isopropyl-N- (2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) -3- (4- (methylamino) piperidin-1-yl) -1H-pyrazolo [4,3-c ]Pyridin-6-amine (GT-D-74) (yellow solid, 0.97 g). 1 H NMR (400 mhz, meod) δ9.38 (s, 1H), 8.03 (d, j=7.1 hz, 1H), 7.80 (s, 1H), 6.59 (d, j=7.1 hz, 1H), 4.89 (s, 1H), 4.30 (d, j=13.0 hz, 2H), 3.89 (d, j=8.7 hz, 2H), 3.67 (d, j=15.3 hz, 2H), 3.59 (s, 1H), 3.39 (s, 3H), 3.37-3.32 (m, 1H), 3.20 (s, 2H), 2.77 (s, 3H), 2.27 (d, j=11.6 hz, 2H), 2.07-1.94 (m, 2H), 1.83 (ddd, j=33.0, 16.1,8.8hz, 4H), 1.54 (d, j=6.5 hz, i.62 s, i.480 s.
Intermediate example 58: preparation of 1-isopropyl-N- (2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) -3- (4- (piperazin-1-yl) piperidin-1-yl) -1H-pyrazolo [4,3-c ] pyridin-6-amine (GT-D-75)
Referring to scheme 26, 1-isopropyl-N- (2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) -3- (4- (piperazin-1-yl) piperidin-1-yl) -1H-pyrazolo [4,3-c]Pyridin-6-amine (GT-D-75) (yellow solid, 1.1 g). 1 H NMR(400MHz,MeOD)δ9.40(s,1H),8.05(d,J＝7.0Hz,1H),7.83(s,1H),6.61 (d, j=7.0 hz, 1H), 4.39 (d, j=12.7 hz, 2H), 3.93 (s, 3H), 3.67 (dd, j=33.6, 15.5hz, 12H), 3.41 (s, 3H), 3.23 (t, j=12.4 hz, 2H), 2.41 (d, j=10.4 hz, 2H), 2.07 (dd, j=23.8, 8.9hz, 4H), 1.79 (s, 2H), 1.57 (d, j=6.4 hz, 6H). LCMS (ESI) calculated values, 535.4; actual measurement 535.5.
Intermediate example 59: preparation of 7-cyclopentyl-N, N-dimethyl-2- ((5- (4- (methylamino) piperidin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-D ] pyrimidine-6-carboxamide (GT-D-79)
Referring to scheme 16, 7-cyclopentyl-N, N-dimethyl-2- ((5- (4- (methylamino) piperidin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d]Pyrimidine-6-carboxamide (GT-D-79) (yellow solid, 800 mg). 1 H NMR (400 mhz, dmso) δ9.38 (s, 1H), 8.77 (s, 1H), 8.15 (d, j=9.1 hz, 1H), 8.03 (d, j=2.9 hz, 1H), 7.45 (dd, j=9.1, 3.0hz, 1H), 6.60 (s, 1H), 4.74 (p, j=8.8 hz, 1H), 3.67 (d, j=12.5 hz, 2H), 3.51 (s, 1H), 3.06 (s, 6H), 2.90-2.80 (m, 1H), 2.72 (t, j=11.1 hz, 2H), 2.47 (s, 3H), 2.43 (d, j=11.5 hz, 2H), 2.05-1.94 (m, 6H), 1.67-1.51 (m, 4H). S (ESI calculated values of 3.463; found 463.2.
Intermediate example 60: preparation of 7-cyclopentyl-N, N-dimethyl-2- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-D ] pyrimidine-6-carboxamide (GT-D-80)
Referring to scheme 16, 7-cyclopentyl-N, N-dimethyl-2- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d]Pyrimidine-6-carboxamide (GT-D-80) (off-white solid, 305 mg). 1 H NMR(400MHz,DMSO)δ9.22(s,1H),8.74(s,1H),8.12(d,J＝9.2Hz,1H),7.98(d,J＝2.8Hz,1H),7.42(dd,J＝9.1,2.9Hz,1H),6.59(s,1H),4.80–4.66(m,1H),3.05(s,6H),2.70–2.66(m,4H),2.63(d,J＝11.8Hz,2H),2.42(s,6H),2.24(d,J＝11.4Hz,1H),1.97(s6H), 1.84 (d, j=11.2 hz, 2H), 1.64 (s, 2H), 1.58-1.50 (m, 2H), 1.23 (s, 1H). LCMS (ESI) calculated, 518.3; found 518.4.
Intermediate example 61: preparation of 5, 7-dimethoxy-2- (4- (piperazin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-51)
Referring to scheme 28, 5, 7-dimethoxy-2- (4- (piperazin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-51) (light yellow solid, 1.0 g) was prepared. 1 H NMR (400 mhz, dmso) δ9.40 (s, 2H), 8.14 (d, j=8.8 hz, 2H), 7.15 (d, j=8.9 hz, 2H), 7.02 (s, 1H), 6.61 (s, 1H), 3.90 (d, j=7.5 hz, 6H), 3.87 (s, 1H), 3.65-3.25 (m, 8H). LCMS (ESI) calculated values 367.2; found, 367.4.
Intermediate example 62: preparation of 5, 7-dimethoxy-2- (4- (4- (methylamino) piperidin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-93)
Referring to scheme 28, 5, 7-dimethoxy-2- (4- (4- (methylamino) piperidin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-93) (yellow solid, 0.64 g) was prepared. 1 H NMR (400 mhz, meod) delta 7.95 (d, j=8.9 hz, 2H), 7.10 (d, j=9.0 hz, 2H), 6.77 (d, j=2.1 hz, 1H), 6.54 (d, j=2.1 hz, 1H), 4.08 (d, j=13.1 hz, 2H), 3.92 (d, j=3.2 hz, 6H), 2.97 (t, j=11.9 hz, 2H), 2.74 (s, 3H), 2.20 (d, j=10.4 hz, 2H), 1.70 (tt, j=12.2, 6.2hz, 2H). LCMS (ESI): calculated value, 395.2; found, 395.3.
Intermediate example 63: preparation of 5, 7-dimethoxy-2- (4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-94)
Referring to scheme 28, 5, 7-dimethoxy-2- (4-) (4- (piperazin-1-yl) piperidin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-94) (yellow solid, 0.26 g). 1 H NMR (400 mhz, dmso) δ11.74 (s, 1H), 8.90 (s, 1H), 8.09 (d, j=8.8 hz, 2H), 7.03 (t, j=10.9 hz, 2H), 6.68 (d, j=2.0 hz, 1H), 6.47 (d, j=1.9 hz, 1H), 3.96 (d, j=12.5 hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.05 (s, 4H), 2.83 (t, j=11.6 hz, 2H), 2.71 (s, 4H), 1.83 (d, j=11.1 hz, 2H), 1.47 (d, j=9.3 hz, 2H). S (ESI). Calculated, 450.3; found, 450.3.
Intermediate example 64: preparation of N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide hydrochloride (GT-D-101)
Referring to scheme 55, N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a]Pyrimidine-3-carboxamide hydrochloride (GT-D-101) (yellow solid, 1.3 g). 1 H NMR (400 mhz, meod) delta 8.55 (d, j=8.0 hz, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.03-6.75 (m, 2H), 4.60 (s, 1H), 3.86-3.80 (m, 8H), 3.58 (dd, j=10.0, 6.5hz, 2H), 3.27-3.17 (m, 2H), 2.39-2.24 (m, 4H). LCMS (ESI) calculated values, 447.2; found, 447.2.
Intermediate example 65: preparation of 1- (4- (4-chloro-1, 2-diphenylbut-1-en-1-yl) phenyl) piperazine (GT-D-104) 
Referring to scheme 31, 1- (4- (4-chloro-1, 2-diphenylbut-1-en-1-yl) phenyl) piperazine (GT-D-104) (yellow solid, 1.6 g) was prepared. 1 H NMR (400 mhz, dmso) delta 7.39 (d, j=7.5 hz, 2H), 7.29 (dd, j=8.4, 7.0hz, 3H), 7.26-7.21 (m, 2H), 7.20-7.16 (m, 3H), 6.70 (d, j=8.9 hz, 2H), 6.63 (d, j=9.0 hz, 2H), 3.42 (t, j=7.3 hz, 2H), 3.21-3.14 (m, 4H), 3.08-2.99 (m, 4H), 2.84 (s, 2H). LCMS (ESI) calculated values, 403.2; found, 403.2.
Intermediate example 66: preparation of 4,4' - (4-chloro-1- (4- (piperazin-1-yl) phenyl) but-1-en-1, 2-diyl) diphenol (GT-D-106)
Referring to scheme 32, 4' - (4-chloro-1- (4- (piperazin-1-yl) phenyl) but-1-en-1, 2-diyl) diphenol (GT-D-106) (brown solid, 0.98 g) was prepared. 1 H NMR (400 mhz, dmso) δ9.37 (d, j=50.2 hz, 2H), 8.70 (s, 1H), 6.97 (dd, j=34.1, 8.4hz, 4H), 6.77-6.58 (m, 6H), 6.52-6.40 (m, 1H), 4.10 (d, j=4.9 hz, 1H), 3.43 (t, j=6.5 hz, 2H), 3.36 (s, 1H), 3.22 (d, j=4.3 hz, 4H), 3.16 (dd, j=10.2, 4.0hz, 4H), 2.81 (t, j=7.3 hz, 2H). LCMS (ESI): calculated values, 435.2; found, 435.2.
Intermediate example 67: preparation of (Z) -4- (1- (4- (2-aminoethoxy) phenyl) -4-chloro-2-phenylbut-1-en-1-yl) phenol (GT-D-186)
Referring to scheme 33, (Z) -4- (1- (4- (2-aminoethoxy) phenyl) -4-chloro-2-phenylbut-1-en-1-yl) phenol (GT-D-186) was prepared (light yellow solid, 100 mg). 1 H NMR (400 mhz, dmso) delta 7.19 (dt, j=14.2, 7.6hz, 6H), 7.07 (d, j=8.5 hz, 1H), 6.96 (d, j=8.7 hz, 1H), 6.75 (dd, j=17.5, 8.6hz, 2H), 6.61 (dd, j=8.7, 6.6hz, 2H), 6.42 (d, j=8.6 hz, 1H), 3.97 (t, j=5.6 hz, 1H), 3.79 (t, j=5.6 hz, 1H), 3.44 (t, j=7.4 hz, 2H), 2.97-2.78 (m, 4H) ·lcms (ESI calculated, 394.2; found 394.2.
Intermediate example 68: preparation of 3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide hydrochloride (GT-D-109)
Referring to scheme 35, 3- (imidazo [1, 2-b) is prepared]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzylAmide hydrochloride (GT-D-109) (off-white solid, 670 mg). 1 H NMR (400 mhz, meod) δ9.10 (dd, j=4.5, 1.3hz, 1H), 8.62 (s, 1H), 8.52 (dd, j=9.3, 1.3hz, 1H), 8.39 (d, j=1.8 hz, 1H), 8.24 (d, j=1.8 hz, 1H), 8.14 (d, j=1.8 hz, 1H), 8.09 (d, j=8.6 hz, 1H), 7.98 (ddd, j=13.9, 8.7,3.2hz, 2H), 7.55 (d, j=8.1 hz, 1H), 4.53 (s, 2H), 3.60 (dd, j=26.0, 12.5hz, 8H), 2.69 (s, 3H). S (ESI) calculated values, 519.2; found 519.4.
Intermediate example 69: preparation of 3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-110)
Referring to scheme 34, 3- (imidazo [1, 2-b) is prepared]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-110) (off-white solid, 930 mg). 1 H NMR (400 mhz, meod) delta 9.10-9.00 (m, 1H), 8.55 (s, 1H), 8.47 (dd, j=9.3, 1.3hz, 1H), 8.22 (d, j=1.8 hz, 1H), 8.15 (d, j=2.4 hz, 1H), 8.05 (dd, j=8.7, 2.4hz, 1H), 7.97 (dd, j=8.0, 1.9hz, 1H), 7.89 (dd, j=9.3, 4.5hz, 1H), 7.65 (t, j=6.5 hz, 1H), 7.59-7.56 (m, 1H), 3.38-3.34 (m, 4H), 3.23-3.14 (m, 4H), 2.68 (s, 3H). LCMS (ESI calculated value, 505.2; found, 505.3.
Intermediate example 70: preparation of 3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-111)
Referring to scheme 34, 3- (imidazo [1, 2-b) is prepared]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-111) (white solid, 1.8 g). 1 H NMR(400MHz,DMSO)δ10.63(s,1H),9.21(s,2H),8.86(dd,J＝4.4,1.1Hz,1H),8.43(s,1H),8.21(dd,J＝14.6,1.9Hz,2H),8.08(s,1H),8.00(dd, j=8.0, 1.6hz, 1H), 7.59-7.53 (m, 3H), 3.00 (d, j=11.7 hz, 3H), 2.78 (s, 2H), 2.61 (s, 3H), 2.54 (t, j=5.4 hz, 3H), 2.11 (d, j=10.0 hz, 2H), 1.70 (dt, j=11.3, 8.1hz, 2H). LCMS (ESI) calculated values 533.2; found 533.2.
Intermediate example 71: preparation of 3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-112)
Referring to scheme 34, 3- (imidazo [1, 2-b) is prepared]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-112) (brown solid, 2.1 g). 1 H NMR (400 mhz, dmso) δ10.60 (s, 1H), 8.74 (dd, j=4.4, 1.5hz, 1H), 8.28 (dd, j=9.2, 1.5hz, 1H), 8.25 (s, 1H), 8.22 (d, j=2.1 hz, 2H), 8.19-8.13 (m, 1H), 7.96 (dd, j=8.0, 1.8hz, 1H), 7.58 (t, j=9.0 hz, 2H), 7.42 (dd, j=9.2, 4.5hz, 1H), 3.49 (d, j=13.0 hz, 4H), 3.15 (s, 6H), 2.98-2.82 (m, 2H), 2.62 (s, 3H), 2.33 (d, j=10.9 hz, 2H), 1.80 (d, j=9.7 hz, 2H): values of (i. 588.3; found, 588.2.
Intermediate example 72: preparation of tert-butyl (4- (4- ((3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) carbamoyl) oxazol-2-yl) pyridin-2-yl) (2, 2-trifluoroethyl) carbamate (GT-D-126)
Referring to scheme 36, tert-butyl (4- (4- ((3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) carbamoyl) oxazol-2-yl) pyridin-2-yl) (2, 2-trifluoroethyl) carbamate (GT-D-126) was prepared (white solid, 2.2 g). 1 HNMR(400MHz,CDCl 3 )δ9.06(s,1H),8.53(d,J＝5.1Hz,1H),8.39(s,1H),8.34(d,J＝5.3Hz,2H),7.72(dd,J＝5.1,1.2Hz,1H),6.84(t,J＝54.7Hz,1H),4.88(q,J＝8.7Hz,2H),4.21(s,1H),3.26(d,J＝12.6Hz,2H),2.77 (td, j=12.5, 2.1hz, 2H), 2.16 (d, j=12.2 hz, 2H), 1.92 (dd, j=12.1, 3.8hz, 2H), 1.58 (s, 9H). LCMS (ESI) calculated, 586.2; found, 586.3.
Intermediate example 73: preparation of (1 r,4 r) -4- (6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -4- (isopropylamino) nicotinamide) cyclohexane-1-carboxylic acid (GT-D-132)
Referring to scheme 38, (1 r,4 r) -4- (6- (5-cyano-1H-pyrrolo [2, 3-b) is prepared]Pyridin-1-yl) -4- (isopropylamino) nicotinamide group) cyclohexane-1-carboxylic acid (GT-D-132) (white solid, 3.1 g). 1 H NMR (400 mhz, dmso) δ12.11 (s, 1H), 8.81 (d, j=1.9 hz, 1H), 8.67 (d, j=2.0 hz, 1H), 8.63-8.55 (m, 2H), 8.52 (d, j=3.9 hz, 1H), 8.37 (d, j=7.6 hz, 1H), 8.07 (s, 1H), 6.89 (d, j=3.9 hz, 1H), 3.77 (dt, j=19.1, 6.3hz, 2H), 2.17 (dd, j=11.2, 7.9hz, 1H), 2.04-1.85 (m, 4H), 1.39 (dd, j=16.9, 8.0hz, 4H), 1.30 (s, 3H), 1.29 (s, 3H). LCMS (ESI calculated values, 447.2; found, 447.2.
Intermediate example 74: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -4- (isopropylamino) -N- (piperidin-4-yl) nicotinamide (GT-D-133)
Referring to scheme 37, 6- (5-cyano-1H-pyrrolo [2, 3-b) is prepared]Pyridin-1-yl) -4- (isopropylamino) -N- (piperidin-4-yl) nicotinamide (GT-D-133) (white solid, 2.8 g). 1 H NMR (400 mhz, meod) delta 8.80 (d, j=1.3 hz, 1H), 8.74 (s, 1H), 8.62 (d, j=1.5 hz, 1H), 8.39 (d, j=4.0 hz, 1H), 7.44 (s, 1H), 7.09 (d, j=4.0 hz, 1H), 4.34-4.04 (m, 2H), 3.52 (d, j=13.1 hz, 2H), 3.17 (dd, j=12.4, 10.3hz, 2H), 2.23 (d, j=11.3 hz, 2H), 1.97 (td, j=14.5, 4.2hz, 2H), 1.39 (d, j=6.4 hz, 6H). LCMS (ESI): calculated values, 404.2; measured, 404.3.
Intermediate example 75: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-D-179)
Referring to scheme 39, N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-D-179) was prepared (brown solid, 1.03 g). 1 H NMR (400 mhz, meod) delta 8.79 (d, j=2.3 hz, 1H), 8.68 (d, j=2.3 hz, 1H), 8.00 (d, j=2.3 hz, 1H), 7.88-7.80 (m, 2H), 7.30 (d, j=9.1 hz, 2H), 6.88 (d, j=2.2 hz, 1H), 3.90 (dd, j=11.4, 5.8hz, 3H), 3.72 (s, 8H), 3.24 (d, j=12.2 hz, 2H), 2.31 (d, j=10.7 hz, 2H), 2.09 (dd, j=16.3, 7.7hz, 2H) ·lcms (ESI calculated, 532.2; found 532.2.
Intermediate example 76: preparation of (R) -5- (3- (3-methyl-2-oxoimidazolidin-1-yl) piperidin-1-yl) -3- ((4- (piperidin-4-yl) phenyl) amino) pyrazine-2-carboxamide (GT-D-197)
Referring to scheme 40, (R) -5- (3- (3-methyl-2-oxoimidazolidin-1-yl) piperidin-1-yl) -3- ((4- (piperidin-4-yl) phenyl) amino) pyrazine-2-carboxamide (GT-D-197) was prepared (yellow solid, 3.0 g). 1 H NMR (400 mhz, dmso) δ11.19 (s, 1H), 7.75 (s, 1H), 7.66 (d, j=7.9 hz, 1H), 7.48 (t, j=10.8 hz, 2H), 7.37-7.29 (m, 1H), 7.14 (d, j=8.4 hz, 2H), 4.32 (dd, j=28.6, 12.2hz, 2H), 3.60 (d, j=10.7 hz, 1H), 3.26 (dd, j=13.7, 7.6hz, 2H), 3.10-2.90 (m, 4H), 2.73 (d, j=14.9 hz, 3H), 2.63-2.54 (m, 2H), 1.76 (ddd, j=33.3, 25.5,11.2hz, 6H), 1.49 (dd, j=20.7, 19.1, 10.6 hz, 2H): calculating the value of (es.384 hz, i.62 s); found, 479.5.
Intermediate example 77: preparation of 5- (piperidin-1-yl) -3- ((4- (piperidin-4-yl) phenyl) amino) pyrazine-2-carboxamide (GT-D-198)
Referring to scheme 41, 5- (piperidin-1-yl) -3- ((4- (piperidin-4-yl) phenyl) amino) pyrazine-2-carboxamide (GT-D-198) (yellow solid, 1.7 g) was prepared. 1 H NMR (400 mhz, dmso) δ11.23 (s, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.49 (d, j=8.5 hz, 2H), 7.28 (s, 1H), 7.14 (d, j=8.5 hz, 2H), 3.66 (d, j=5.3 hz, 4H), 3.15 (s, 2H), 3.03-2.93 (m, 2H), 2.54 (d, j=14.1 hz, 2H), 1.64 (d, j=11.7 hz, 4H), 1.57 (d, j=3.8 hz, 4H), 1.47 (td, j=12.3, 3.6hz, 2H) ·s (ESI calculated values, 381.2; found, 381.2.
Intermediate example 78:4, 9-dioxo-4, 9-dihydronaphtho [2,3-b]Preparation of furan-2-carboxylic acid (GT-D-200)
Referring to scheme 42, 4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] is prepared]Furan-2-carboxylic acid (GT-D-200) (brown solid, 130 mg). 1 H NMR (400 mhz, dmso) δ8.14 (ddd, j=7.1, 4.3,3.3hz, 2H), 8.03-7.85 (m, 2H), 7.69 (s, 1H). LCMS (ESI) calculated, 243.0; found, 243.0.
Intermediate example 79: preparation of (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino xide (GT-S-50)
Referring to scheme 16, (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino oxide (GT-S-50) (yellow solid, 950 mg) was prepared. 1 H NMR (400 MHz, DMSO-d 6): delta ppm 12.76 (s, 1H), 9.23 (br, 2H), 8.91 (d, 3H), 8.38-8.32 (m, 2H), 8.00 (d, 1H), 7.49 (s, 1H), 6.77 (s, 1H), 3.83 (s, 3H), 3.32-3.24 (m, 4H), 3.12-2.97 (m, 4H), 2.13 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H). LCMS (ESI): calculated value, 597.2; found, 597.1.
Intermediate example 80: preparation of (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino oxide (GT-S-51)
Referring to scheme 16, (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino oxide (GT-S-51) (yellow solid, 1.1 g) was prepared. 1 H NMR(400MHz,CD 3 OD): delta ppm 8.94-8.90 (br, 3H), 8.30 (s, 1H), 8.10-8.07 (br, 1H), 7.35 (s, 1H), 6.89 (s, 1H), 3.91 (s, 3H), 3.39-3.24 (m, 3H), 2.91 (t, J=15.6 Hz, 2H), 2.82 (s, 3H), 2.30-2.19 (m, 11H), 1.98-1.84 (m, 11H), 1.98-1.84 (m, 2H): LCMS (ESI): calculated value, 625.2; found, 625.1.
Intermediate example 81: preparation of (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino oxide (GT-S-52)
Referring to scheme 16, (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino oxide (GT-S-52) was prepared (yellow solid, 150mg, yield 108.88%). 1 H NMR(400MHz,DMSO-d 6 ) Delta ppm 9.10-8.80 (m, 2H), 8.41 (s, 1H), 8.05-7.95 (m, 1H), 7.60-7.50 (m, 2H), 7.48-7.36 (m, 3H), 7.20-7.10 (m, 2H), 6.85-6.80 (m, 1H), 3.80-3.62 (m, 6H), 3.60-3.40 (m, 6H), 3.35-3.30 (m, 2H), 2.85-2.60 (m, 2H), 2.38-2.25 (m, 2H), 2.20-1.90 (m, 11H). LCMS (ESI): calculated value, 680.2; found, 680.1.
Intermediate example 82: preparation of 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (piperazin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-7)
Referring to scheme 45, 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (piperazin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-7) was prepared (yellow solid, 300mg, yield 21%). 1 HNMR(400MHz,DMSO-d 6 ) Delta ppm 8.67-8.61 (m, 2H), 8.38 (s, 1H), 8.08-8.05 (br, 2H), 7.85 (s, 1H), 6.96 (d, j=11.6 hz, 1H), 5.94 (s, 1H), 5.20-5.11 (m, 1H), 4.44 (d, j=6.4 hz, 2H), 3.52-3.49 (m, 4H), 2.86-2.78 (m, 4H), 2.57-2.53 (m, 2H), 2.11 (s, 3H), 1.58-1.51 (m, 8H), 0.90 (t, j=9.6 hz, 3H). LCMS (ESI): calculated value, 528.3; found, 528.5.
Intermediate example 83: preparation of 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (methylamino) piperidin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-8)
Referring to scheme 43, 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (methylamino) piperidin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-8) was prepared (light yellow solid, 1.8 g). 1 H NMR(400MHz,DMSO-d 6 ) Delta ppm 8.69-8.57 (m, 4H), 8.63 (s, 1H), 8.15-8.08 (m, 4H), 7.82 (br, 1H), 7.11 (d, J=8.8 Hz, 1H), 5.91 (s, 1H), 5.17-5.10 (m, 1H), 4.48-4.41 (m, 4H), 3.30-3.28 (br, 1H), 2.96 (t, J=12.6 Hz, 2H), 2.59 (t, J=5.2 Hz, 3H), 2.54-2.49 (m, 4H), 2.14 (s, 3H), 2.09-2.07 (m, 2H), 1.57-1.49 (m, 8H), 0.88 (t, J=7.4 Hz, 3H): S (ESI calculated value, 556.3; found, 556.5.
Intermediate example 84: preparation of 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-9)
Referring to scheme 44, 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-9) was prepared (pale yellow solid, 2.0 g). 1 H NMR(400MHz,DMSO-d 6 ) Delta ppm 11.99 (br, 1H), 9.40-9.37 (br, 1H), 8.78 (br, 1H), 8.67 (s, 1H), 8.45-8.40 (m, 2H), 8.24 (s, 1H), 7.88 (s, 1H), 7.40 (d, J=12 Hz, 1H), 5.99 (s, 1H), 5.24-5.15 (m, 1H), 4.66-4.62 (m, 2H), 4.45-4.44 (br, 2H), 3.77-3.18 (m, 7H), 3.25-3.18 (m, 2H), 2.97-2.90 (m, 2H), 2.58-2.52 (m, 4H), 2.37-2.33 (br, 2H), 2.17 (s, 3H), 2.10-2.02 (m, 2H), 1.57 (m, 2H), 3.77-3.18 (m, 7H), 3.25-3.18 (m, 2H), 2.97-2.90 (m, 3H), 2.17 (m, 3H); found 611.7.
Intermediate example 85: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (piperazin-1-ylmethyl) - [1,1' -biphenyl)]Preparation of 3-carboxamide (GT-S-10)
Referring to scheme 47, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (piperazin-1-ylmethyl) - [1,1' -biphenyl) is prepared]3-carboxamide (GT-S-10) (yellow solid, 1.4 g). 1 H NMR(400MHz,DMSO-d 6 ) Delta ppm 11.99 (br, 1H), 9.40-9.37 (br, 1H), 8.78 (br, 1H), 8.67 (s, 1H), 8.45-8.40 (m, 2H), 8.24 (s, 1H), 7.88 (s, 1H), 7.40 (d, J=12 Hz, 1H), 5.99 (s, 1H), 5.24-5.15 (m, 1H), 4.66-4.62 (m, 2H), 4.45-4.44 (br, 2H), 3.77-3.18 (m, 7H), 3.25-3.18 (m, 2H), 2.97-2.90 (m, 2H), 2.58-2.52 (m, 4H), 2.37-2.33 (br, 2H), 2.17 (s, 3H), 2.10-2.02 (m, 2H), 1.57 (m, 2H), 3.77-3.18 (m, 7H), 3.25-3.18 (m, 2H), 2.97-2.90 (m, 3H), 2.17 (m, 3H); found 611.7.
Intermediate example 86: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (piperazin-1-yl) - [1,1' -biphenyl ] -3-carboxamide (GT-S-11)
Referring to scheme 48, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (piperazin-1-yl) - [1,1' -biphenyl) is prepared ]3-carboxamide (GT-S-11) (white solid, 2.6 g). 1 H NMR(400MHz,DMSO-d 6 ) δ8.21 (t, j=6.0 hz, 1H), 7.54 (d, j=11.6 hz, 2H), 7.3 (s, 1H), 7.20 (s, 1H), 7.07 (d, j=11.2 hz, 2H), 4.31 (d, j=6 hz, 2H), 3.86 (d, j=13.6 hz, 2H), 3.35-3.12 (m, 15H), 2.24 (d, j=6.4 hz, 6H), 2.14 (s, 2H), 1.71-1.48 (m, 4H), 0.86 (t, j=9.2 hz, 3H). LCMS (ESI) calculated values, 558.3; found, 558.5.
Intermediate example 87: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (4- (methylamino) piperidin-1-yl) - [1,1' -biphenyl)]Preparation of 3-carboxamide (GT-S-12)
Referring to scheme 49, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (4- (methylamino) piperidin-1-yl) - [1,1' -biphenyl) is prepared]3-carboxamide (GT-S-12) (white solid, 1.8 g). 1 H NMR(400MHz,DMSO-d 6 ) Delta 8.16 (t, j=4.8 hz, 1H), 7.45 (d, j=8.8 hz, 2H), 7.33 (s, 1H), 7.16 (s, 1H), 6.98 (d, j=8.8 hz, 2H), 5.86 (s, 1H), 4.29 (d, j=4.8 hz, 2H), 3.82 (d, j=10.4 hz, 2H), 3.65 (d, j=12.4 hz, 2H), 3.25 (t, j=11.2 hz, 3H), 3.10-3.01 (m, 4H), 2.76 (t, j=11.6 hz, 2H), 2.45-2.38 (m, 1H), 2.29 (s, 3H), 2.21 (d, j=6.8 hz, 6H), 2.11 (s, 3H), 1.89-1.85 (m, 2H), 1.66 (m-1.64 hz, 2H), 1.64 (m, 3H), 1.32 (t, 1.38H); found, 586.2.
Intermediate example 88: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (4- (piperidin-4-yl) piperazin-1-yl) - [1,1' -biphenyl)]Preparation of 3-carboxamide (GT-S-13)
Referring to scheme 50, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (4- (piperidin-4-yl) piperazin-1-yl) - [1,1' -biphenyl) is prepared]3-carboxamide (GT-S-13) (white solid, 1.6 g). 1 H NMR(400MHz,DMSO-d 6 ) Delta 8.18 (t, j=2.0 hz, 1H), 7.47 (d, j=8.4 hz, 2H), 7.33 (s, 1H), 7.16 (s, 1H), 6.98 (d, j=8.0 hz, 2H), 5.86 (s, 1H), 4.29 (d, j=4.0 hz, 2H), 4.14-4.06 (m, 1H), 3.82 (d, j=9.2 hz, 2H), 3.41-3.36 (m, 2H), 3.29 (d, j=12.0 hz, 3H), 3.14-2.98 (m, 9H), 3.62 (s, 4H), 2.28-2.21 (m, 7H), 2.11 (s, 3H), 1.68-1.64 (m, 4H), 1.53-1.50 (m, 2H), 1.26-1.24 (m, 2H), 3.83 (m, 6H): 6 hz, 3H; found, 642.0.
Intermediate example 89: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-14)
Referring to scheme 51, N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-14) was prepared (yellow solid, 341 mg). 1 H NMR(400MHz,DMSO-d 6 ) δ10.22 (s, 1H), 9.13 (s, 2H), 7.88 (d, j=12 Hz, 1H), 7.48 (d, j=19.2 Hz, 1H), 7.43 (s, 1H), 7.28 (d, j=11.6 Hz, 1H), 7.03 (t, j=16 Hz, 3H), 6.30 (t, j=11.6 Hz, 2H), 4.32-4.07 (m, 2H), 3.86 (t, j=5.2 Hz, 2H), 3.73 (s, 1H), 3.50 (d, j=14.4 Hz, 6H), 3.26 (s, 4H), 1.97 (d, j=15.6 Hz, 2H), 1.42-1.36 (m, 2H). Lcm (ESI) calculated values, 547.3; found, 547.0.
Intermediate example 90: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (methylamino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-15)
Referring to scheme 52, N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (methylamino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-15) was prepared (yellow solid, 601 mg). 1 H NMR(400MHz,DMSO-d 6 ) Delta 9.40 (s, 3H), 7.49 (t, j=11.6 Hz, 2H), 7.11 (d, j=10.4 Hz, 1H), 6.81 (d, j=8.4 Hz, 1H), 6.45 (d, j=9.2 Hz, 2H), 6.34 (t, j=11.6 Hz, 1H), 5.94 (d, j=11.6 Hz, 1H), 5.83 (s, 1H), 3.75 (s, 2H), 3.60 (d, j=18.4 Hz, 4H), 3.26 (d, j=13.2 Hz, 3H), 2.86 (s, 1H), 2.57 (t, j=16.4 Hz, 2H), 2.38 (s, 3H), 1.91 (d, j=13.6 Hz, 1H), 1.67 (t, j=12.4 Hz, 2H), 1.56 (t, j=13.6 Hz, 2H), 1.27 (s, 2H); actual measurement, 575.0.
Intermediate example 91: preparation of (R) -6- (2- (3-fluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) imidazo [1,2-b ] pyridazine (GT-S-17)
Referring to scheme 53, (R) -6- (2- (3-fluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) imidazo [1,2-b is prepared]Pyridazine (GT-S-17) (yellow solid, 800 mg). 1 H NMR (400 mhz, dmso-d 6) delta 8.17 (s, 1H), 7.89 (d, j=6.4 hz, 1H), 5.57 (s, 2H), 7.54 (d, j=10.2 hz, 1H), 7.42-7.36 (m, 2H), 7.05 (t, j=8.0 hz, 1H), 6.82-6.74 (m, 2H), 5.15 (d, j=4.0 hz, 1H), 3.98,3.95 (dd, j=6.4, 6.0 hz, 1H), 3.71-3.60 (m, 6H), 2.99 (s, 4H), 2.53-2.44 (m, 1H), 2.03 (d, j=6.8 hz, 2H), 1.89-1.85 (m, 1H), 1.23 (s, 1H). LCMS (ESI) calculated values, 444.2; found, 444.3.
Intermediate example 92: preparation of (R) -1- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) -N-methylpiperidin-4-amine (GT-S-18)
Reference scheme 54, preparationTo give (R) -1- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1, 2-b)]Pyridazin-3-yl) pyridin-2-yl) -N-methylpiperidin-4-amine (GT-S-18) (yellow solid, 790 mg). 1 H NMR(400 MHz,CD 3 OD) delta 8.61 (s, 1H), 8.20 (s, 1H), 7.40 (t, j=7.6 hz, 2H), 7.18-7.02 (m, 6H), 5.25 (s, 1H), 4.58 (s, 2H), 4.15 (t, j=9.2 hz, 1H), 3.68 (s, 1H), 3.39 (s, 1H), 3.35 (s, 1H), 2.86 (s, 3H), 2.36 (s, 1H), 2.33 (s, 2H), 2.21 (s, 3H), 2.06 (d, j=3.6 hz, 3H), 1.85-1.82 (m, 2H). LCMS (ESI): calculated values, 472.3; found 472.3.
Intermediate example 93: preparation of the following intermediate compounds
Referring to the procedure of scheme 57, the enantiomeric mixture products obtained according to step 8 of scheme 57 were resolved by Supercritical Fluid Chromatography (SFC) to give the above two intermediate compounds, respectively (retention times of 8.232 min and 9.400 min, respectively, on the analytical method). The analytical methods, preparation methods and conditions of SFC are shown below.
The analysis method and conditions of SFC are as follows:
the preparation method of SFC comprises the following steps:
one of the intermediates obtained (GT-M-160_p1) (white solid, 565 mg): 1 H NMR(400 MHz,DMSO)δ9.11(s,1H),7.23–7.06(m,3H),6.84(d,J＝6.7 Hz,2H),6.62(dd,J＝15.5,5.3 Hz,2H),6.55–6.43(m,3H),6.21(d,J＝8.6 Hz,2H),4.13(d,J＝4.9 Hz,1h) 3.28 (s, 2H), 3.04-2.91 (m, 2H), 2.91-2.83 (m, 4H), 2.80-2.70 (m, 4H), 2.11 (dd, j=12.3, 6.4 hz, 1H), 1.71 (d, j=7.5 hz, 1H). LCMS (ESI) calculated, 385.23 found, 385.30. (retention time on analytical method was 8.232 min).
Another intermediate (GT-M-160_p2) (white solid, 595, mg): 1 h NMR (400 mhz, dmso) δ9.10 (s, 1H), 7.14 (dd, j=15.2, 7.8 hz, 3H), 6.84 (d, j=6.9 hz, 2H), 6.66-6.59 (m, 2H), 6.50 (dd, j=14.1, 8.3 hz, 3H), 6.22 (d, j=8.4 hz, 2H), 4.14 (d, j=4.6 hz, 1H), 3.30-3.23 (m, 2H), 2.97 (dd, j=15.6, 9.6 hz, 2H), 2.90 (d, j=5.0 hz, 4H), 2.80 (d, j=4.5 hz, 4H), 2.11 (dd, j=12.2, 6.8 hz, 1H), 1.72 (s, 1H). S (ESI) calculated values, 385.30 measured. (retention time on analytical method was 9.400 min).
Intermediate example 94: preparation of the following intermediate compounds
Referring to the procedure of scheme 58, the enantiomeric mixture product obtained according to step 6 of scheme 58 was resolved by Supercritical Fluid Chromatography (SFC) to give the above two intermediate compounds, respectively (retention times of 1.763min and 3.506min, respectively, on the analytical method). The analytical methods, preparation methods and conditions of SFC are shown below.
The analysis method and conditions of SFC are as follows:
the preparation method of SFC comprises the following steps:
one of the intermediates obtained (GT-M-173_P1) (white solid, 555 mg): 1 H NMR(400MHz,DMSO)δ9.33(s,1H),7.22(dd,J＝20.1,17.2Hz,3H),6.88(d,J＝45.0Hz,2H),6.71(d,J＝83hz, 1H), 6.64 (d, j=8.6 hz, 2H), 6.44 (d, j=8.5 hz, 2H), 6.39-6.22 (m, 2H), 4.39 (t, j=11.1 hz, 1H), 4.30-4.06 (m, 2H), 3.55 (dt, j=39.1, 19.2hz, 1H), 2.95 (d, j=4.8 hz, 4H), 2.83 (d, j=4.5 hz, 4H). LCMS (ESI) calculated, 387.21 actual measurement, 387.40. (retention time on analytical method was 1.763 min).
Another intermediate (GT-M-173_p1) (white solid, 495 mg): 1 h NMR (400 mhz, dmso) δ9.33 (s, 1H), 7.22 (dd, j=20.1, 17.2hz, 3H), 6.88 (d, j=45.0 hz, 2H), 6.71 (d, j=8.3 hz, 1H), 6.64 (d, j=8.6 hz, 2H), 6.44 (d, j=8.5 hz, 2H), 6.39-6.22 (m, 2H), 4.39 (t, j=11.1 hz, 1H), 4.30-4.06 (m, 2H), 3.55 (dt, j=39.1, 19.2hz, 1H), 2.95 (d, j=4.8 hz, 4H), 2.83 (d, j=4.5 hz, 4H) s (ESI) calculated values, 387.21 measured values, 387.40. (retention time on analytical method was 3.506 min).
Intermediate example 95: preparation of N- (3- (difluoromethyl) -1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazo [1,5-a ] pyrimidine-3-carboxamide (GT-04349)
Referring to scheme 55, the title compound GT-04349 (white solid, 15mg, yield 67.08%) was prepared. 1 HNMR(400MHz,MeOD)δ8.45(d,J＝8.0Hz,1H),8.33(s,1H),8.22(s,1H),6.97–6.59(m,2H),4.50(s,2H),3.69(dd,J＝35.3,32.6Hz,10H),3.16(s,1H),2.85(s,3H),2.29(s,4H).LCMS(ESI)C 21 H 27 F 2 N 8 O 2 + [M+H] + Calculated 461.22, found 461.2.
Intermediate example 96: preparation of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- (piperidin-4-ylmethoxy) pyrido [4,3-D ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (GT-D-204)
Referring to scheme 60, the mesh is preparedThe title compound GT-D-204 (yellow solid, 0.92g, yield 86.79%) 1 HNMR (400 mhz, cdcl 3) delta 8.99 (s, 1H), 7.84 (dd, j=9.2, 5.7hz, 1H), 7.55 (d, j=2.5 hz, 1H), 7.39 (d, j=2.4 hz, 1H), 7.29 (dd, j=14.0, 5.2hz, 1H), 5.32 (q, j=6.9 hz, 2H), 4.55 (dd, j=29.6, 12.4hz, 2H), 4.42 (s, 2H), 4.33 (d, j=6.2 hz, 2H), 3.70 (s, 2H), 3.53 (s, 3H), 3.22 (d, j=12.2 hz, 2H), 2.80 (s, 1H), 2.71 (t, j=11.2 hz, 2H), 2.04-1.91 (m, 9H), 1.53 (s, 2H), 4.701, 62 s, 38701, i.
Intermediate example 97: preparation of (R) -5- (2, 5-difluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) pyrazolo [1,5-a ] pyrimidine (GT-D-191)
Referring to scheme 61, the title compound GT-D-191 (red solid, 262mg, yield 81.75%) 1 HNMR (400 mhz, dmso) δ9.48 (s, 2H), 8.66 (d, j=8.0 hz, 1H), 8.49 (s, 1H), 7.79-6.24 (m, 7H), 5.44 (d, j=4.0 hz, 1H), 4.20-3.95 (m, 2H), 3.84-3.77 (m, 5H), 3.20 (s, 4H), 2.10 (s, 2H), 1.93 (d, j=8.0 hz, 1H). LCMS (ESI) calculated, 462.22 actual measured, 462.2.
Intermediate example 98:2- (6, 7-dihydro-5H-pyrrolo [1, 2-c)]Preparation of imidazol-1-yl) -2- (4-fluoro-1-oxo-6- (4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-219)
Referring to scheme 62, the title compound GT-D-219 (yellow solid, 1.1g, yield 113.53%) 1 HNMR (400 mhz, meod) delta 8.92 (s, 1H), 8.03-7.82 (m, 5H), 7.77 (dd, j=10.0, 1.2hz, 1H), 7.58 (d, j=4.0 hz, 1H), 7.34 (d, j=4.0 hz, 1H), 4.95 (d, j=17.2 hz, 2H), 4.65 (d, j=17.2 hz, 1H), 4.44-4.29 (m, 2H), 4.00 (d, j=12.0 hz, 3H), 3.92-3.65 (m, 10H), 3.10-2.97 (m, 1H), 2.94-2.82 (m, 1H), 2.78-2.48 (m, 6H) s (ESI) calculated, 641.28 measured, 641.4.
Intermediate example 99:2- (6, 7-dihydro-5H-pyrrolo [1,2-c]Preparation of imidazol-1-yl) -2- (4-fluoro-1-oxo-6- (4- (4- (piperidin-4-yl) piperazin-1-yl) phenyl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-217) 
Referring to scheme 63, the title compound GT-D-217 was prepared (yellow solid, 800mg, 99.45% yield). 1 H NMR (400 mhz, meod) delta 8.90 (s, 1H), 7.88 (s, 1H), 7.66 (d, j=8.6 hz, 3H), 7.57-7.51 (m, 1H), 7.32-7.26 (m, 1H), 7.18-6.89 (m, 3H), 4.91 (d, j=16.0 hz, 1H), 4.82-4.75 (m, 1H), 4.58 (d, j=17.0 hz, 1H), 4.38-4.33 (m, 2H), 4.01 (s, 2H), 3.78 (s, 2H), 3.64 (d, j=12.0 hz, 2H), 3.38 (s, 2H), 3.26 (s, 2H), 3.18-3.12 (m, 2H), 3.07-2.99 (m, 1H), 2.91-2.84 (m, 1H), 4.82-4.75 (m, 1H), 4.38-4.33 (m, 2H), 4.01 (s, 2H), 3.64 (d, j=12.0 hz, 2H), 3.38 (s, 2H).
Intermediate example 99: preparation of 2- (6- (4- ((1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -N- (thiazol-2-yl) acetamide (GT-D-222)
Referring to scheme 62, steps 2 through 5, the title compound GT-D-222 (an off-white solid, 0.56g, 109.7%) was prepared using the starting compound (CAS number: 2407965-04-0) and the compound (CAS number: 942189-80-2). 1 HNMR (400 mhz, meod) δ8.90 (s, 1H), 7.85 (d, j=1.2 hz, 1H), 7.69-7.59 (m, 3H), 7.54 (d, j=4.0 hz, 1H), 7.29 (d, j=4.0 hz, 1H), 6.81 (d, j=8.0 hz, 2H), 4.91 (d, j=10.0 hz, 1H), 4.87-4.81 (m, 1H), 4.74 (s, 1H), 4.62-4.50 (m, 2H), 4.35 (dd, j=12.0, 7.2hz, 2H), 3.79 (dd, j=10.0, 2.4hz, 1H), 3.40 (s, 2H), 3.06-2.81 (m, 2H), 2.77-2.61 (m, 2H), 2.33 (d, j=10.0 hz, 1H), 4.62-4.50 (m, 2H), 4.35 (dd, j=12.0, 7.2hz, 2H), 3.06-2.81 (m, 2H), and calculated values (i.37H).
Intermediate example 100:2- (6, 7-dihydro-5H-pyrrolo [1, 2-c)]Imidazole-like materialPreparation of 1-yl) -2- (4-fluoro-6- (4- (4- (methylamino) piperidin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-221)
Referring to scheme 62, steps 2 through 5, the title compound GT-D-221 (yellow solid, 0.72g, yield 105.4%) was prepared using the starting compound (CAS number: 2407965-04-0) and the compound (CAS number: 2235416-80-3). 1 HNMR (400 mhz, meod) δ8.91 (s, 1H), 7.96 (d, j=1.2 hz, 1H), 7.92 (d, j=3.2 hz, 3H), 7.77 (dd, j=10.0, 1.2hz, 1H), 7.55 (d, j=3.6 hz, 1H), 7.30 (d, j=3.6 hz, 1H), 6.51 (s, 1H), 4.96 (d, j=17.2 hz, 1H), 4.88 (s, 1H), 4.83 (s, 1H), 4.63 (d, j=17.2 hz, 1H), 4.34 (dt, j=12.0, 7.2hz, 2H), 3.93 (d, j=12.0 hz, 2H), 3.85 (t, j=11.2 hz, 2H), 3.63 (dd, j=20.0, 9.6hz, 98 hz), 4.83 (s, 1H), 4.63 (d, j=17.2 hz, 1H), 4.34 (d, 1H), 4.34 (dt, j=12.2 hz, 1H), 3.85 (2H), 3.82 m (2H).
Intermediate example 101:2- (6- (4- (3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) phenyl) -4-fluoro-1-oxo-isoindolin-2-yl-2- (6, 7-dihydro-5H-pyrrolo [1, 2-c)]Preparation of imidazol-1-yl) -N- (thiazol-2-yl) acetamide (GT-D-224) 
Referring to scheme 62, the title compound GT-D-224 (as an off-white solid, 619mg, 105.0% yield) was prepared using the starting compound (CAS number 1146427-86-2) instead of the compound (CAS number 2762613-62-5). 1 HNMR (400 mhz, meod) δ8.90 (s, 1H), 7.88 (d, j=1.0 hz, 1H), 7.65 (dd, j=10.0, 7.2hz, 3H), 7.50 (d, j=4.0 hz, 1H), 7.24 (d, j=4.0 hz, 1H), 7.07 (d, j=8.0 hz, 2H), 4.91 (d, j=16.0 hz, 1H), 4.55 (d, j=16.0 hz, 1H), 4.35 (dd, j=12.0, 8.0hz, 2H), 4.22 (s, 2H), 4.10 (q, j=7.2 hz, 1H), 3.80 (d, j=10.0 hz, 2H), 3.16 (t, j=12.0 hz, 2H), 3.09-2.94 (m, 1H), 2.92-2.77 (m-2H), 4.37 (m, 2H), and values calculated (lcm, 37 s, 2H).
Intermediate example 102: preparation of 2- (6- (4- ((1R, 4R) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -N- (thiazol-2-yl) acetamide (GT-D-223)
Referring to scheme 62, steps 2 through 5, the title compound GT-D-223 (as an off-white solid, 1.3g, 101.7% yield) was prepared using the starting compound (CAS number: 2407965-04-0) and the compound (CAS number: 2654825-27-9). 1 HNMR (400 mhz, meod) delta 8.90 (s, 1H), 7.84 (d, j=4.0 hz, 1H), 7.64-7.58 (m, 4H), 7.35 (d, j=4.0 hz, 1H), 6.81 (d, j=8.7 hz, 2H), 4.92 (s, 1H), 4.87-4.84 (m, 1H), 4.74 (s, 1H), 4.67-4.48 (m, 2H), 4.39-4.32 (m, 2H), 3.80-3.77 (m, 1H), 3.40 (s, 3H), 3.11-2.96 (m, 1H), 2.95-2.82 (m, 1H), 2.72-2.66 (m, 2H), 2.32 (d, j=8.hz, 1H), 2.10 (d, j=12.0 hz, 1H) calculated values of s, 35, 37 hz.
Intermediate example 103:2- (6- (4- (4- (3, 3-difluoropiperidin-4-yl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -2- (6, 7-dihydro-5H-pyrrolo [1, 2-c)]Preparation of imidazol-1-yl) -N- (thiazol-2-yl) acetamide (GT-D-218)
Referring to scheme 63, steps 3 through 6, the title compound GT-D-218 (off-white solid, 645mg, yield 103.32%) was prepared using starting compound 2 and tert-butyl 3, 3-difluoro-4-oxopiperidine-1-carboxylate. 1 H NMR (400 mhz, meod) delta 8.92 (s, 1H), 7.93 (d, j=1.2 hz, 1H), 7.84 (d, j=8.8 hz, 2H), 7.74 (dd, j=10.0, 1.2hz, 1H), 7.69-7.55 (m, 3H), 7.42 (d, j=4.0 hz, 1H), 4.95 (s, 2H), 4.68 (d, j=16.0 hz, 1H), 4.45-4.24 (m, 2H), 3.88 (t, j=8.0 hz, 2H), 3.76 (s, 4H), 3.67-3.49 (m, 6H), 3.33 (d, j=12.0 hz, 1H), 3.10-2.96 (m, 1H), 2.96-2.81 (m, 1H), 2.77-2.59 (m, 2H), 2.24 (m, 2H), 3.67-4.24 (m, 2H), 3.88 (t, j=8.0 hz, 2H), 3.37 hz, 2.37H)
Intermediate example 104: preparation of N- (5- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) benzo [ D ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-D-208)
Referring to scheme 64, the title compound GT-D-208 was prepared (yellow solid, 1.7g, yield 109%). 1 HNMR (400 mhz, meod) delta 8.79 (s, 1H), 8.48 (d, j=8.0 hz, 1H), 8.30 (t, j=8.0 hz, 1H), 8.04 (d, j=7.6 hz, 1H), 7.71 (s, 1H), 3.56-3.48 (m, 3H), 3.47-3.41 (m, 1H), 3.28-3.20 (m, 2H), 2.45 (dd, j=14.4, 3.6hz, 2H), 2.23-2.11 (m, 2H), 1.71 (s, 6H) s (ESI) calculated, 449.18 values, 449.2.
Intermediate example 105: preparation of N- (6- (2-hydroxypropan-2-yl) -2- (piperidin-4-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-D-210)
Referring to scheme 65, the title compound GT-D-210 was prepared (yellow solid, 1.52g, yield 109.4%). 1 H NMR(400MHz,D 2 O) δ8.20 (s, 1H), 8.10 (s, 1H), 8.04 (d, j=4.0 hz, 2H), 7.85-7.79 (m, 1H), 7.49 (s, 1H), 4.67-4.62 (m, 1H), 3.57 (d, j=13.2 hz, 2H), 3.20 (dd, j=12.8, 10.0hz, 2H), 2.34-2.14 (m, 4H), 1.54 (s, 6H). LCMS (ESI) calculated, 448.20 actual measured, 448.2.
Intermediate example 106:2- (6- (4- (3, 3-difluoro-4- (piperazin-1-yl) piperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -2- (6, 7-dihydro-5H-pyrrolo [1, 2-c)]Preparation of imidazol-1-yl) -N- (thiazol-2-yl) acetamide (GT-D-220)
Referring to scheme 66, the title compound GT-D-220 was prepared (as a brown solid, 0.5g, 66.6% yield). 1 HNMR(400MHz,MeOD)δ7.83(s,1H),7.65(s,1H),7.60-7.58(m,3H),7.44(d,J＝3.6Hz,1H),7.15(d,J＝4.0Hz,1H),7.06(d, j=8.0 hz, 2H), 4.85 (s, 1H), 4.81 (s, 1H), 4.25 (d, j=16.0 hz, 1H), 4.12-4.04 (m, 2H), 3.98-3.91 (m, 2H), 3.19 (d, j=4.0 hz, 4H), 3.16-2.76 (m, 8H), 2.65-2.56 (m, 3H), 2.11-2.06 (m, 1H), 2.00-1.86 (m, 1H) LCMS (ESI) calculated values, 677.26 actual measured values, 677.4.
Example 1: preparation of 3- (5- (((3S, 4R) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03297)
Referring to the procedure of scheme 11, step 2, the intermediate compound 1- ((3 s,4 r) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d) prepared in example 1]Pyrimidine-4-amine (205 mg,0.51 mmol) was dissolved in anhydrous DMF (10 mL), and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (171 mg,0.51 mmol) and DIEA (0.25 mL,1.52 mmol) were added sequentially to the reaction solution. The reaction was warmed to 50 ℃, stirred for 18 hours, and TLC detected the completion of the reaction. The reaction solution is cooled to room temperature and purified by preparative high-phase liquid chromatography to obtain the target compound 3- (5- (((3S, 4R) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d))]Pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl piperidine-2, 6-dione (white solid, 182mg, yield 51%). 1 HNMR (400 mhz, meod) delta 8.35 (s, 1H), 7.85 (d, j=8.0 hz, 1H), 7.77 (s, 1H), 7.67 (d, j=8.0 hz, 1H), 7.57 (d, j=8.0 hz, 2H), 7.32 (t, j=8.0, 7.5hz, 2H), 7.13-7.04 (m, 3H), 7.04-6.98 (m, 2H), 5.41-5.26 (m, 2H), 5.09 (dd, j=12.0, 4.0hz, 1H), 4.57-4.45 (m, 4H), 3.84-3.72 (m, 3H), 3.69-3.63 (m, 1H), 3.48-3.42 (m, 1H), 2.89-2.78 (m, 1H), 2.72-2.67 (m, 2H), 5.41-5.26 (m, 2H), 5.09 (dd, j=12.0, 4.0hz, 1H), 3.48-3.72 (m, 2H), 2.38 (LC/LC) and (LC value of the value of (LC/LC) 36 H 34 FN 8 O 4 + [M+H] + 661.3; found 661.3.
Example 2: preparation of 3- (5- (((3R, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03331)
Referring to scheme 11, step 2 and the procedure of example 1, 1- ((3R, 4S) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d is used]Pyrimidin-4-amine and 3- (5- (bromo)Methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione was prepared to give the title compound (GT-03331) (white solid, 175mg, yield 61.5%). 1 H NMR(400MHz,MeOD)δ8.27(s,1H),7.85(d,J＝7.8Hz,1H),7.76(s,1H),7.66(d,J＝7.9Hz,1H),7.56(d,J＝8.6Hz,2H),7.32(t,J＝8.0Hz,2H),7.15–6.95(m,5H),5.29(t,J＝33.3Hz,2H),5.09(dd,J＝13.4,5.1Hz,1H),4.52(dd,J＝14.4,10.0Hz,4H),3.74(d,J＝11.8Hz,2H),3.66–3.53(m,1H),3.42(t,J＝12.4Hz,1H),3.11(dt,J＝33.7,16.9Hz,1H),2.91–2.63(m,2H),2.42(dt,J＝18.2,10.9Hz,2H),2.15–2.05(m,1H).LCMS(ESI)C 36 H 34 FN 8 O 4 + [M+H] + Calculated 661.27, measured 661.2.
Example 3: preparation of 3- (5- (((3R, 4R) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03287)
Referring to scheme 11, step 2 and the procedure of example 1, 1- ((3R, 4R) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d is used]Pyrimidine-4-amine and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-03287) (white solid, 23mg, 46% yield). 1 H NMR(400MHz,MeOD)δ8.31(s,1H),7.82(d,J＝7.8Hz,1H),7.74(s,1H),7.64(d,J＝7.9Hz,1H),7.53(s,2H),7.36–7.27(m,2H),7.17–6.95(m,5H),5.29(d,J＝45.4Hz,2H),5.07(dd,J＝13.4,5.1Hz,1H),4.60–4.35(m,4H),3.79(d,J＝2.5Hz,1H),3.64–3.50(m,1H),3.22(s,2H),2.86–2.74(m,1H),2.68(d,J＝15.5Hz,1H),2.42(ddd,J＝22.0,16.3,11.7Hz,3H),2.13–2.03(m,1H).LCMS(ESI)C 36 H 34 FN 8 O 4 + [M+H] + Calculated 661.27, measured 661.3.
Example 4: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide (GT-02912)
Referring to scheme 11, step 2 and the procedure of example 1, N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (piperazin-1-yl) prepared in intermediate example 12 was used) Pyridazine-3-carboxamide (15.00 mg,0.034 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (11.47 mg,0.034 mmol) gave the title compound (GT-02912) (white solid, 10mg, yield 41.32%). 1 H NMR(400MHz,DMSO)δppm 11.00(s,1H),8.65(d,J＝8.2Hz,1H),7.96-7.82(m,4H),7.76(d,J＝7.9Hz,1H),7.45(d,J＝9.6Hz,1H),7.37(d,J＝2.4Hz,1H),7.12(dd,J＝8.8,2.4Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.48(m,7H),3.92-3.82(m,1H),3.60(m,3H),3.12(m,3H),2.93(dd,J＝15.2,10.5Hz,1H),2.61(d,J＝16.7Hz,2H),2.10(dd,J＝10.8,1.1Hz,2H),2.06-1.99(m,1H),1.90(dd,J＝12.9,2.5Hz,2H),1.64(dd,J＝24.1,10.8Hz,2H),1.51(dd,J＝22.7,9.8Hz,2H)。LCMS(ESI)m/z:C 36 H 38 ClN 8 O 5 + [M+H] + Calculated, 697.26; found, 697.30.
Example 5: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide (GT-02932)
Referring to the procedure of scheme 11, step 2 and example 1, 6- (3, 8-diazabicyclo [ 3.2.1) was prepared using the procedure of scheme 5 and intermediate example 12]Octane-8-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide (15.00 mg,0.032 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione hydrochloride (10.83 mg,0.032 mmol) gave the title compound (GT-02932) (white solid, 9.00mg, yield 37.97%). 1 H NMR(400MHz,DMSO)δppm 11.00(s,1H),8.60(d,J＝8.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.86(d,J＝8.8Hz,2H),7.74(d,J＝7.7Hz,1H),7.69(d,J＝7.7Hz,1H),7.39(d,J＝2.4Hz,1H),7.18-7.10(m,2H),5.11(dd,J＝13.3,5.0Hz,1H),4.64(s,2H),4.57-4.51(m,1H),4.39(t,J＝11.8Hz,1H),4.32(s,2H),3.92-3.84(m,1H),3.64-3.59(m,3H),3.12(m,2H),2.97-2.83(m,2H),2.73-2.60(m,2H),2.42(dd,J＝13.0,4.9Hz,1H),2.10(dd,J＝19.2,8.2Hz,3H),1.93(d,J＝13.0Hz,2H),1.71-1.61(m,2H),1.53(dd,J＝22.9,12.5Hz,2H)。LCMS(ESI)m/z:C 38 H 40 ClN 8 O 5 + [M+H] + Calculated value, 723.27 The method comprises the steps of carrying out a first treatment on the surface of the Found, 723.20.
Example 6: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide (GT-02987)
Referring to the procedure of scheme 11, step 2 and example 1, 6- (3, 8-diazabicyclo [ 3.2.1) was prepared using the procedure of scheme 5 and intermediate example 12]Octane-3-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide (10.00 mg,0.021 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (7.22 mg,0.021 mmol) gave the title compound (GT-02987) (white solid, 6.00mg, yield 37.96%). 1 H NMR(400MHz,DMSO)δppm 10.94(s,1H),9.27(dd,J＝14.3,6.6Hz,2H),8.63-8.46(m,1H),7.78(d,J＝8.8Hz,2H),7.66(s,2H),7.31(d,J＝2.4Hz,1H),7.06(dd,J＝8.8,2.4Hz,1H),5.09-5.02(m,1H),4.48-4.39(m,2H),4.30(m,2H),4.00-3.89(m,2H),3.81-3.77(m,1H),3.54-3.52(m,3H),3.06(dd,J＝7.3,3.2Hz,4H),2.96-2.75(m,1H),2.62-2.53(m,1H),2.31(dd,J＝32.9,6.7Hz,2H),2.06-1.92(m,4H),1.83(d,J＝11.2Hz,2H),1.60-1.52(m,2H),1.44(dd,J＝22.4,9.1Hz,2H)。LCMS(ESI)m/z:C 38 H 40 ClN 8 O 5 + [M+H] + Calculated, 723.27; found, 723.30.
Example 7: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide (GT-02933)
Referring to the procedure of scheme 11, step 2 and example 1, 6- (3, 6-diazabicyclo [ 3.1.1) prepared by the procedure of scheme 5 and intermediate example 12 was used]Heptane-6-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide (15.00 mg,0.033 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (11.17 mg,0.033 mmol) gave the title compound (GT-02933) (white solid, 8.00mg, yield 33.38%). 1 H NMR(400MHz,DMSO)δppm 11.00(s,1H),8.60(d,J＝8.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.86(d,J＝8.8Hz,2H),7.74(d,J＝7.7Hz,1H),7.69(d,J＝7.7Hz,1H),7.39(d,J＝2.4Hz,1H),7.18-7.10(m,2H),5.11(dd,J＝13.3,5.0Hz,1H),4.64(s,2H),4.57-4.51(m,1H),4.39(t,J＝11.8Hz,1H),4.32(s,2H),3.92-3.84(m,1H),3.64-3.59(m,3H),3.12(qd,J＝7.4,4.3Hz,2H),2.97-2.83(m,2H),2.73-2.60(m,2H),2.42(dd,J＝13.0,4.9Hz,1H),2.10(dd,J＝19.2,8.2Hz,3H),1.93(d,J＝13.0Hz,2H),1.71-1.61(m,2H),1.53(dd,J＝22.9,12.5Hz,2H)。LCMS(ESI)m/z:C 37 H 38 ClN 8 O 5 + [M+H] + Calculated, 709.26; found, 709.30.
Example 8: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide (GT-02934)
Referring to the procedure of scheme 11, step 2 and example 1, 6- (3, 6-diazabicyclo [ 3.1.1) prepared by the procedure of scheme 5 and intermediate example 12 was used]Heptane-3-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide (15.00 mg,0.033 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (11.17 mg,0.033 mmol) gave the title compound (GT-02934) (white solid, 9.00mg, yield 37.55%). 1 H NMR(400MHz,DMSO)δppm 11.00(s,1H),8.67(t,J＝7.8Hz,1H),8.05-7.88(m,2H),7.85(dt,J＝8.4,5.3Hz,2H),7.75-7.67(m,1H),7.38(s,1H),7.32-7.10(m,2H),5.12(dd,J＝11.7,6.5Hz,1H),4.94-4.74(m,2H),4.54-4.50(m,1H),4.38(d,J＝11.3Hz,1H),4.10(d,J＝33.2Hz,2H),3.92-3.84(m,1H),3.61-3.56(m,3H),3.12-3.09(m,2H),3.01-2.84(m,2H),2.68-2.57(m,2H),2.39(dd,J＝13.1,4.3Hz,1H),2.10-2.00(m,3H),1.94-1.85(m,2H),1.71-1.60(m,2H),1.56-1.46(m,2H)。LCMS(ESI)m/z:C 37 H 38 ClN 8 O 5 + [M+H] + Calculated, 709.26; found, 709.20.
Example 9: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazine-3-carboxamide (GT-02989)
Reference scheme 11 step 2 and example 1 the procedure of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) pyridazine-3-carboxamide (20.00 mg,0.038 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (12.87 mg,0.038 mmol) prepared by the method of reference scheme 5 and intermediate example 12 gave the title compound (GT-02989) (white solid, 12.00mg, yield 39.49%). 1 H NMR(400MHz,DMSO)δppm 10.99(s,1H),8.60(d,J＝8.2Hz,1H),7.87-7.77(m,4H),7.72(d,J＝8.2Hz,1H),7.44(d,J＝9.7Hz,1H),7.37(d,J＝2.3Hz,1H),7.13(dd,J＝8.8,2.3Hz,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.65(d,J＝12.9Hz,2H),4.56-4.30(m,5H),3.87(dd,J＝11.5,7.2Hz,1H),3.69-3.55(m,5H),2.95(m,5H),2.71-2.54(m,2H),2.47-2.30(m,2H),2.19(d,J＝9.6Hz,2H),2.10(d,J＝10.6Hz,2H),2.04-1.95(m,1H),1.89(d,J＝9.7Hz,2H),1.66(dt,J＝24.5,11.4Hz,4H),1.51(dd,J＝22.6,10.1Hz,2H).LCMS(ESI)m/z:C 41 H 47 ClN 9 O 5 + [M+H] + Calculated, 780.33; found 780.30.
Example 10: preparation of N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide (GT-02988)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of scheme 5 and intermediate example 12 was followed to prepare N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (piperazin-1-yl) nicotinamide (10.00 mg,0.021 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (7.20 mg,0.021 mmol) to give the title compound (GT-02988) (white solid, 9.00mg, yield 56.98%). 1 H NMR(400MHz,DMSO)δppm 8.62(d,J＝2.3Hz,1H),7.96(dt,J＝9.0,2.6Hz,1H),7.89(d,J＝8.8Hz,1H),7.65(t,J＝9.4Hz,2H),7.58(s,1H),7.46(d,J＝7.6Hz,1H),7.20(d,J＝2.4Hz,1H),7.00(dd,J＝8.8,2.4Hz,1H),6.85(d,J＝9.1Hz,1H),4.74(dd,J＝10.3,4.7Hz,1H),4.69-4.58(m,1H),4.43(dd,J＝27.3,17.6Hz,1H),4.31(s,1H),4.04(d,J＝9.2Hz,1H),3.63(d,J＝3.9Hz,7H),2.79(s,3H),2.23-2.11(m,2H),2.10-1.76(m,2H),1.11(s,12H)。LCMS(ESI)m/z:C 39 H 43 ClN 7 O 5 + [M+H] + Calculated, 724.29; found, 724.30.
Example 11: preparation of 3- (5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02821)
Referring to scheme 11, step 2 and the method of example 1, 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] is used]Imidazol-6-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1231930-57-6) (20.00 mg,0.042 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (14.09 mg,0.042 mmol) gave the title compound (GT-02821) (white solid, 7.00mg, yield 22.34%). 1 H NMR(400MHz,DMSO)δppm 10.97(s,1H),10.06(s,1H),8.69(d,J＝3.8Hz,1H),8.30(s,1H),8.20(d,J＝8.6Hz,2H),7.67(dd,J＝14.3,6.9Hz,3H),7.53(s,1H),7.43(d,J＝7.9Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.84(dt,J＝14.0,7.1Hz,1H),4.44(d,J＝17.3Hz,1H),4.31(d,J＝17.3Hz,1H),3.58(s,2H),3.46(s,2H),2.99-2.81(m,3H),2.73(s,1H),2.6-2.57(m,4H),2.42-2.32(m,5H),2.05-1.94(m,2H),1.62(d,J＝6.9Hz,6H).LCMS(ESI)m/z:C 39 H 41 F 2 N 10 O 3 + [M+H] + Calculated, 734.33; found, 735.30.
Example 12: preparation of 7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (GT-02822)
Referring to scheme 11, procedure 2 and example 1, 7-cyclopentyl-N, N-dimethyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d ] is employed]Pyrimidine-6-carboxamide (CAS number 1211441-98-3) (20.00 mg,0.046 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (15.52 mg,0.046 mmol) gave the title compound (GT-02822) (white solid, 5.00mg, yield 15.41%). 1 H NMR(400MHz,DMSO)δppm 10.99(s,1H),9.37(s,1H),8.77(s,1H),8.15(d,J＝9.1Hz,1H),8.01(d,J＝2.7Hz,1H),7.70(d,J＝7.7Hz,1H),7.58(s,1H),7.49(d,J＝7.8Hz,1H),7.42(dd,J＝9.1,2.7Hz,1H),6.59(s,1H),5.12(dd,J＝13.2,5.0Hz,1H),4.80-4.66(m,1H),4.46(d,J＝17.4Hz,1H),4.33(d,J＝17.3Hz,1H),3.66(s,2H),3.10(d,J＝37.3Hz,10H),3.00-2.84(m,2H),2.64-2.54(m,5H),2.46-2.32(m,3H),1.97(s,4H),1.68-1.56(m,2H).LCMS(ESI)m/z:C 37 H 43 N 10 O 4 + [M+H] + Calculated, 691.34; found, 691.30.
Example 13: preparation of 3- (5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02812)
Referring to scheme 11, step 2 and the method of example 1, 6-acetyl-8-cyclopentyl-5-methyl-2- ((5- (piperazin-1-yl) pyridin-2-yl) amino) pyrido [2,3-d]Pyrimidine-7 (8H) -one (CAS number 571190-30-2) (20.00 mg,0.045 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (15.07 mg,0.045 mmol) gave the title compound (GT-02812) (yellow solid, 10.00mg, yield 31.16%). 1 H NMR(400MHz,DMSO)δppm 10.98(s,1H),10.07(s,1H),8.95(s,1H),8.04(s,1H),7.84(d,J＝8.0Hz,1H),7.70(d,J＝7.2Hz,1H),7.59(s,1H),7.52-7.43(m,2H),5.90-5.74(m,1H),5.18-5.06(m,1H),4.47(d,J＝14.7Hz,1H),4.34(d,J＝19.7Hz,1H),3.67(s,2H),3.20-3.13(m,4H),2.96-2.85(m,3H),2.75-2.55(m,10H),2.30(s,3H),1.82(m,4H),1.61-1.54(m,2H).LCMS(ESI)m/z:C 38 H 42 N 9 O 5 + [M+H] + Calculated, 704.32; found, 704.40.
Example 14: preparation of 3- (5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepino [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03160)
Referring to scheme 11, step 2 and the method of example 1, 8-fluoro-5- (4- ((methylamino) methyl) phenyl) -2,3,4, 6-tetrahydro-1H-azepino [5,4,3-cd ] is used]Indol-1-one (CAS number 283173-50-2) (15.00 mg,0.046 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidineThe title compound (GT-03260) (white solid, 3.00mg, yield 10.93%) was obtained from (15.64 mg,0.046 mmol) of-2, 6-dione. 1 H NMR(400MHz,DMSO)δppm 11.89(s,1H),11.01(s,1H),8.29(t,J＝5.7Hz,1H),7.91(d,J＝5.9Hz,1H),7.81(dd,J＝10.7,8.1Hz,4H),7.74–7.69(m,2H),7.43(dd,J＝10.9,2.4Hz,1H),7.36(dd,J＝9.1,2.4Hz,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.59–4.45(m,3H),4.38(dd,J＝17.5,9.4Hz,2H),4.31(dd,J＝12.6,6.1Hz,1H),3.61–3.57(m,1H),3.13–3.06(m,3H),2.98–2.85(m,1H),2.59(t,J＝9.0Hz,4H),2.46–2.35(m,1H),2.04–1.95(m,1H).LCMS(ESI)m/z:C 33 H 31 FN 5 O 4 + [M+H] + Calculated, 578.23; found, 578.23.
Example 17: preparation of 3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02811)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of scheme 3 was followed to prepare (2- ((5-chloro-2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (20.00 mg,0.035 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2, 6-dione (11.83 mg,0.035 mmol) using the procedure of scheme 3 to give the title compound (GT-02811) (white solid, 10.00mg, 17.25%). 1 H NMR(400MHz,DMSO)δppm 11.71(s,1H),11.00(s,1H),9.12(d,J＝131.8Hz,1H),8.42(s,1H),8.20(s,1H),7.87(s,1H),7.79(t,J＝8.5Hz,2H),7.60(dd,J＝13.5,7.7Hz,1H),7.46-7.37(m,2H),7.21(t,J＝7.2Hz,1H),6.81(s,1H),6.65(s,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.43(dd,J＝51.4,17.6Hz,4H),3.88(d,J＝11.4Hz,3H),3.79(s,3H),3.63-3.58(m,4H),3.11(m,2H),2.92(m,4H),2.61(d,J＝16.4Hz,1H),2.45-2.37(m,1H),2.21(d,J＝9.8Hz,2H),2.04-1.99(m,1H),1.90(dt,J＝13.5,10.1Hz,2H),1.80(s,3H),1.77(s,3H).LCMS(ESI)m/z:C 42 H 50 ClN 9 O 5 P + [M+H] + Calculated, 826.33; found, 826.30.
Example 18: preparation of 3- (5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (GT-03327)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03327) (white solid, 28.00mg, yield 53.83%) was prepared using 4- (4-fluoro-3- (piperazine-1-carbonyl) benzyl) phthalazin-1 (2H) -one (CAS number 763111-47-3) (30.00 mg,0.082 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (27.61 mg,0.082 mmol). 1 H NMR(400MHz,DMSO)δppm 12.59(s,1H),11.00(s,1H),8.32-8.18(m,1H),7.96(d,J＝7.9Hz,1H),7.92-7.85(m,2H),7.85-7.79(m,2H),7.76(d,J＝7.6Hz,1H),7.46(dd,J＝7.0,4.3Hz,1H),7.40(dd,J＝6.4,1.9Hz,1H),7.25(t,J＝9.0Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.62-4.27(m,7H),3.59(m,3H),3.11(m,3H),3.03-2.85(m,2H),2.61(d,J＝17.1Hz,1H),2.42(m,1H),2.08-1.95(m,1H).LCMS(ESI)m/z:C 34 H 32 FN 6 O 5 + [M+H] + Calculated, 623.23; found, 623.30.
Example 19: preparation of 2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide (GT-03328)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03328) (white solid, 30.00mg, yield 54.45%) was prepared using (S) -2- (4- (piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide (CAS number 1038915-60-4) (30.00 mg,0.094 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (38.03 mg,0.113 mmol). 1 H NMR(400MHz,DMSO)δppm 10.98(s,1H),9.24(s,1H),8.61(s,1H),8.14-7.97(m,4H),7.95-7.83(m,2H),7.78(s,2H),7.50(d,J＝8.4Hz,2H),7.30-7.20(m,1H),5.07(dd,J＝13.1,5.0Hz,1H),4.49(d,J＝15.9Hz,2H),4.37(d,J＝17.7Hz,1H),3.58-3.54(m,2H),3.40(d,J＝8.3Hz,1H),3.33-3.26(m,1H),3.07(dd,J＝7.4,4.2Hz,2H),2.94-2.80(m,1H),2.60(d,J＝16.3Hz,1H),2.50(d,J＝1.2Hz,1H),2.45-2.31(m,1H),2.02-1.89(m,3H),1.72(dt,J＝14.8,6.6Hz,1H).LCMS(ESI)m/z:C 33 H 33 N 6 O 4 + [M+H] + Calculated, 577.25; found, 577.30.
Example 20: preparation of N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide (GT-03337)
Referring to scheme 11, procedure 2 and the procedure of example 1, the procedure of scheme 5 and intermediate example 12 was used to prepare N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (piperazin-1-yl) pyridazine-3-carboxamide (30.00 mg,0.064 mmol) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (25.88 mg,0.077 mmol) to give the title compound (GT-03337) (white solid, 30.00mg, yield 63.38%). 1 H NMR(400MHz,DMSO)δppm 11.01(s,1H),8.28(d,J＝9.2Hz,1H),7.97-7.89(m,3H),7.81(q,J＝7.9Hz,2H),7.49(d,J＝9.6Hz,1H),7.24(d,J＝2.3Hz,1H),7.03(dd,J＝8.8,2.4Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.61(d,J＝12.9Hz,2H),4.54-4.45(m,4H),4.38(d,J＝17.6Hz,1H),4.01(d,J＝9.2Hz,1H),3.59(dd,J＝6.6,2.6Hz,3H),3.11(dd,J＝7.4,4.3Hz,3H),2.97-2.88(m,1H),2.64-2.56(m,1H),2.47-2.37(m,1H),2.05-1.98(m,1H),1.22(s,6H),1.14(s,6H).LCMS(ESI)m/z:C 38 H 42 ClN 8 O 5 + [M+H] + Calculated, 725.29; found, 725.30.
Example 21: preparation of 3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02652)
Referring to scheme 11, procedure 2 and example 1, 1- (3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d prepared according to example 2 was used as a reference intermediate]Pyrimidine-4-amine and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-02652) (white solid, 501mg, 28% yield). 1 H NMR(500MHz,CD 3 OD)δ10.99(s,1H),8.27(s,1H),7.75(d,J＝7.7Hz,1H),7.71–7.64(m,3H),7.59(s,1H),7.47–7.40(m,2H),7.21–7.11(m,5H),5.39–5.18(m,1H),5.12(dd,J＝13.3,5.1Hz,1H),5.05–4.84(m,1H),4.49(d,J＝17.5Hz,1H),4.36(d,J＝17.4Hz,1H),3.99(s,2H),3.23–2.99(m,2H),2.97–2.85(m,1H),2.61(d,J＝16.7Hz,2H),2.46–2.21(m,3H),2.15–1.92(m,2H).LCMS(ESI)m/z:C 36 H 33 FN 8 O 4 + [M+H] + Calculated 661.27, measured 661.3.
Example 22: preparation of 3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02742)
Referring to scheme 11, procedure 2 and example 1, 3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-d ] prepared in intermediate example 2 was used]Pyrimidine-4-amine hydrochloride and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-02742) (white solid, 422mg, yield 24%). 1 H NMR(500MHz,DMSO)δ11.00(s,1H),10.85(s,1H),8.38(s,1H),7.89(s,1H),7.84(d,J＝7.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.64(d,J＝8.6Hz,2H),7.49–7.40(m,2H),7.24–7.08(m,5H),5.14(dd,J＝13.2,5.1Hz,1H),5.09–4.99(m,1H),4.59–4.33(m,4H),3.07–2.85(m,2H),2.70–2.53(m,4H),2.48–2.27(m,3H),2.17(d,J＝11.6Hz,2H),2.08–1.95(m,1H).LCMS(ESI)m/z:C 36 H 35 N 8 O 4 + [M+H] + Calculated 643.28, measured 643.3.
Example 23: preparation of 3- (5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02744)
Referring to scheme 11, procedure 2 and example 1, using (R) -3- (4-phenoxyphenyl) -1- (piperidin-3-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-amine (CAS number 1022150-12-4) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-02744) (white solid, 422mg, yield 24%). LCMS (ESI) m/z C 36 H 35 N 8 O 4 + [M+H] + Calculated 643.28, measured 643.3.
Example 24: preparation of N- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (GT-02746)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-02746) (white solid, 5mg, 12% yield) was prepared using N- (tert-butyl) -3- ((5-methyl-2- ((4- (2- (piperazin-1-yl) ethoxy) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-002) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 7. 1 H NMR(500MHz,DMSO)δ11.03(d,J＝10.2Hz,1H),10.50(s,1H),9.97(s,1H),8.00–7.69(m,7H),7.60(dd,J＝20.0,12.1Hz,2H),7.31(d,J＝9.0Hz,2H),6.94(d,J＝8.5Hz,2H),5.18–5.10(m,1H),4.54–4.32(m,5H),3.46(s,11H),2.98–2.89(m,1H),2.61(d,J＝17.0Hz,1H),2.47–2.38(m,1H),2.18(s,3H),2.04–1.96(m,1H),1.09(s,9H).LCMS(ESI)m/z:C 41 H 50 N 9 O 6 S + [M+H] + Calculated 796.36, measured 796.3.
Example 25: preparation of N- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (GT-02753)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-02753) (white solid, 5mg, yield 13%) was prepared using N- (tert-butyl) -3- ((5-methyl-2- ((4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-003) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 9. 1 H NMR(500MHz,DMSO)δ11.15(s,1H),11.03(s,1H),10.49(s,1H),9.93(s,1H),8.02–7.78(m,6H),7.71(d,J＝7.8Hz,1H),7.66–7.51(m,2H),7.36(t,J＝12.9Hz,2H),7.14(d,J＝8.4Hz,2H),5.16(dd,J＝13.3,5.0Hz,1H),4.68–4.29(m,4H),3.44(d,J＝4.6Hz,2H),3.06(d,J＝11.0Hz,2H),2.99–2.86(m,1H),2.75(t,J＝12.0Hz,1H),2.62(d,J＝17.3Hz,1H),2.47–2.38(m,1H),2.16(d,J＝19.1Hz,3H),2.15–1.98(m,3H),1.91(d,J＝12.7Hz,2H),1.09(d,J＝4.8Hz,9H).LCMS(ESI)m/z:C 40 H 47 N 8 O 5 S + [M+H] + Calculated 751.34, found 751.3.
Example 26: preparation of N- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (GT-02755)
Referring to scheme 11, procedure 2 and the method of example 1, the title compound (GT-02755) (white solid, 5mg, yield 13%) was prepared using N- (tert-butyl) -3- ((5-methyl-2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-004) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 10. 1 H NMR(500MHz,DMSO)δ11.47(s,1H),11.03(s,1H),10.33(s,1H),9.88(s,1H),7.96(s,1H),7.93(s,1H),7.90(s,1H),7.85(d,J＝7.8Hz,1H),7.81(d,J＝7.6Hz,1H),7.69(d,J＝7.8Hz,1H),7.63(s,1H),7.55(t,J＝8.0Hz,1H),7.27(d,J＝8.8Hz,2H),6.93(d,J＝8.5Hz,2H),5.16(dd,J＝13.3,5.0Hz,1H),4.57–4.47(m,3H),4.41(t,J＝15.7Hz,1H),3.75(s,2H),3.60(dtd,J＝13.2,6.6,4.1Hz,1H),3.13(ddd,J＝13.3,10.4,8.9Hz,5H),2.98–2.86(m,1H),2.67–2.59(m,1H),2.47–2.39(m,1H),2.17(s,3H),2.07–2.00(m,1H),1.09(s,9H).LCMS(ESI)m/z:C 39 H 46 N 9 O 5 S + [M+H] + Calculated 752.33, measured 752.4.
Example 27: preparation of N- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (GT-02757)
Referring to scheme 11, procedure 2 and the procedure of example 1, the title compound (GT-02757) (white solid, 5mg, 13% yield) was prepared using N- (tert-butyl) -3- ((5-methyl-2- ((6- (piperazin-1-yl) pyridazin-3-yl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-M-17) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 8. 1 H NMR(500MHz,DMSO)δ12.07(s,1H),11.03(s,1H),9.88(s,1H),9.48(s,3H),8.16(d,J＝6.5Hz,1H),8.08(t,J＝9.2Hz,2H),7.95(d,J＝11.4Hz,1H),7.82(s,2H),7.73(s,1H),7.70(d,J＝7.8Hz,2H),7.64(t,J＝7.9Hz,1H),5.15(dd,J＝13.2,5.1Hz,1H),4.61–4.45(m,3H),4.36(dd,J＝24.5,14.7Hz,3H),3.50(dd,J＝34.2,21.3Hz,4H),3.19(s,2H),2.97–2.86(m,1H),2.62(d,J＝17.5Hz,1H),2.46–2.37(m,1H),2.26(s,3H),2.06–1.97(m,1H),1.13(s,9H).LCMS(ESI)m/z:C 37 H 44 N 11 O 5 S + [M+H] + Calculated 754.32, measured 754.3.
Example 28: preparation of 4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide (GT-02956)
Referring to scheme 11, step 2 and the procedure of example 1, (R) -N- (5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3, 4-c) prepared in intermediate example 24 was used]Pyrazol-3-yl) -4- (piperazin-1-yl) benzamide (GT-M-08) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-02956) (white solid, 5mg, 69% yield). 1 H NMR(400MHz,DMSO)δ11.19(d,J＝27.9Hz,1H),11.02(s,1H),10.72(d,J＝9.0Hz,1H),7.94(dd,J＝8.9,2.9Hz,2H),7.88(d,J＝4.0Hz,1H),7.85(d,J＝7.8Hz,1H),7.80–7.73(m,1H),7.46–7.32(m,5H),7.05(dd,J＝9.0,2.4Hz,2H),5.15(dd,J＝13.2,5.0Hz,1H),5.10(d,J＝10.3Hz,1H),4.80(dd,J＝18.8,13.2Hz,1H),4.61–4.35(m,8H),4.03(d,J＝13.0Hz,2H),3.35–3.30(m,8H),2.98–2.88(m,1H),2.65–2.56(m,1H),2.43(dd,J＝13.1,4.4Hz,1H),2.07–1.95(m,1H).LCMS(ESI)m/z:C 39 H 41 N 8 O 6 + [M+H] + Calculated 717.31, measured 717.3.
Example 29: preparation of 3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02967)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f) prepared in intermediate example 4 was employed][1,2,4]Triazolo [4,3-a ]][1,4]Diazepam-6-yl) -1- (piperazin-1-yl) ethan-1-one and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidin-2, The 6-dione was prepared to give the target compound (GT-02967) (white solid, 72mg, yield 22%). 1 H NMR(400MHz,DMSO)δ11.45–11.12(m,1H),11.01(s,1H),7.92–7.80(m,2H),7.79–7.70(m,1H),7.50(d,J＝8.5Hz,2H),7.43(d,J＝8.3Hz,2H),5.15(dd,J＝13.2,5.0Hz,1H),4.69–4.22(m,8H),3.77–3.60(m,3H),3.20–3.13(m,1H),3.02–2.84(m,2H),2.68–2.56(m,5H),2.47–2.44(m,1H),2.42(s,3H),2.06–1.96(m,1H),1.63(s,3H).LCMS(ESI)m/z:C 37 H 38 ClN 8 O 4 S + [M+H] + Calculated 725.24, found 725.2.
Example 30: preparation of 4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile (GT-02968)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-02968) (white solid, 5mg, 20% yield) was prepared using 4- ((2, 4-dichloro-5-methoxyphenyl) amino) -6-methoxy-7- (3- (piperazin-1-yl) propoxy) quinoline-3-carbonitrile (CAS number 380843-81-2) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 HNMR(400MHz,MeOD)δ8.87(s,1H),8.02(s,1H),7.88(d,J＝7.9Hz,1H),7.83(s,1H),7.75–7.69(m,1H),7.68(d,J＝9.2Hz,1H),7.40(d,J＝7.2Hz,2H),5.17(dd,J＝13.3,5.2Hz,1H),4.56(d,J＝8.7Hz,2H),4.46(t,J＝5.4Hz,2H),4.37(s,2H),4.08(s,3H),3.94(s,3H),3.58–3.39(m,6H),2.98–2.86(m,2H),2.84–2.75(m,2H),2.64–2.41(m,4H),2.23–2.12(m,2H).LCMS(ESI)m/z:C 39 H 40 Cl 2 N 7 O 6 + [M+H] + Calculated 772.24, measured 772.2.
Example 31: preparation of 4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-02969)
Referring to scheme 11, procedure 2 and example 1, N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (piperazin-1-ylmethyl) benzamide (CAS number 404844-02-6) and 3- (5- (bromomethyl) -1- Oxo-isoindolin-2-yl) piperidine-2, 6-dione was prepared to give the title compound (GT-02969) (white solid, 5mg, 30% yield). 1 HNMR(500MHz,DMSO)δ11.02(s,1H),10.37(s,1H),9.48(d,J＝1.6Hz,1H),9.21(s,1H),9.02(d,J＝8.0Hz,1H),8.93(d,J＝4.5Hz,1H),8.62(d,J＝5.1Hz,1H),8.16(s,1H),8.06(d,J＝8.3Hz,2H),8.02–7.95(m,1H),7.92(s,1H),7.86–7.73(m,4H),7.59(d,J＝5.2Hz,1H),7.48(dd,J＝8.2,2.0Hz,1H),7.23(d,J＝8.6Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.58–4.33(m,6H),3.52(s,8H),2.97–2.87(m,1H),2.62(t,J＝12.8Hz,1H),2.48–2.36(m,1H),2.24(s,3H),2.05–1.95(m,1H).LCMS(ESI)m/z:C 42 H 42 N 9 O 4 + [M+H] + Calculated 736.34, measured 736.3.
Example 32: preparation of (Z) -3- (5- (((2- (4- (4-chloro-1, 2-diphenylbut-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02970)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-02970) (white solid, 5mg, yield 28%) was prepared using (Z) -2- (4- (4-chloro-1, 2-diphenylbut-1-en-1-yl) phenoxy) -N-methylethan-1-amine (CAS number: 110503-61-2) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ7.90(d,J＝7.8Hz,1H),7.73(s,1H),7.65(d,J＝8.2Hz,1H),7.42–7.34(m,2H),7.34–7.27(m,3H),7.23–7.10(m,5H),6.87(d,J＝8.7Hz,2H),6.68(d,J＝8.8Hz,2H),5.18(dd,J＝13.3,5.2Hz,1H),4.67–4.45(m,4H),4.32–4.21(m,2H),3.63–3.46(m,2H),3.40(t,J＝7.3Hz,2H),3.00–2.86(m,6H),2.83–2.75(m,1H),2.50(qd,J＝13.2,4.6Hz,1H),2.24–2.13(m,1H).LCMS(ESI)m/z:C 39 H 38 ClN 3 O 4 + [M+H] + Calculated 648.26, measured 648.3.
Example 33: preparation of (Z) -3- (5- (((2- (4- (1, 2-diphenylbut-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02971)
Referring to scheme 11, step 2 and the procedure of example 1, the method of (Z) -2- (4- (1, 2-diphenylbut-1-en-1-yl) phenoxy) -N-methyl was usedEthyl-1-amine (CAS number 31750-48-8) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-02971) (white solid, 5mg, yield 27%). 1 H NMR(400MHz,MeOD)δ7.90(d,J＝7.8Hz,1H),7.75(s,1H),7.66(d,J＝7.9Hz,1H),7.39–7.32(m,2H),7.30–7.24(m,1H),7.23–7.19(m,2H),7.18–7.05(m,5H),6.86–6.80(m,2H),6.71–6.63(m,2H),5.17(dd,J＝13.3,5.2Hz,1H),4.55(q,J＝17.4Hz,2H),4.27(t,J＝4.7Hz,1H),4.17–4.10(m,1H),3.56(s,1H),3.41–3.31(m,3H),2.98–2.86(m,3H),2.83–2.76(m,1H),2.74(s,1H),2.57–2.49(m,1H),2.45(q,J＝7.5Hz,2H),2.23–2.12(m,1H),0.90(t,J＝7.4Hz,3H).LCMS(ESI)m/z:C 39 H 40 N 3 O 4 + [M+H] + Calculated 614.30, measured 614.3.
Example 34: preparation of 8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-02972)
Referring to scheme 11, step 2 and the procedure of example 1, 9-ethyl-6, 6-dimethyl-11-oxo-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] prepared in intermediate example 45 was used]Carbazole-3-carbonitrile (GT-D-113) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-02972) (white solid, 5mg, yield 20%). 1 H NMR(400MHz,MeOD)δ8.41(d,J＝8.3Hz,1H),8.20(s,1H),7.90–7.81(m,2H),7.69(s,1H),7.62(d,J＝7.5Hz,1H),7.55(d,J＝8.2Hz,1H),7.39(s,1H),5.18(dd,J＝13.1,5.3Hz,1H),4.54–4.47(m,2H),4.00(s,2H),3.49–3.36(m,6H),3.00–2.88(m,4H),2.86–2.73(m,5H),2.61–2.43(m,2H),2.38–2.13(m,4H),2.03–1.93(m,2H),1.80(s,6H),1.34(t,J＝7.5Hz,3H).LCMS(ESI)m/z:C 44 H 48 N 7 O 4 + [M+H] + Calculated 738.38, measured 738.3.
Example 35: preparation of 3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02973)
Referring to the procedure of scheme 11, step 2 and example 1, 5-chloro-N prepared by the procedure of scheme 3 and intermediate example 9 was used 2 - (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-02973) (white solid, 5mg, yield 65%). 1 H NMR(400MHz,MeOD)δ11.02(s,1H),10.92(s,1H),9.61(s,1H),8.45–8.34(m,2H),8.30(s,1H),7.91(s,1H),7.88–7.82(m,2H),7.79(d,J＝8.0Hz,1H),7.63(t,J＝7.8Hz,1H),7.45(s,1H),7.38(t,J＝7.7Hz,1H),6.82(s,1H),5.15(dd,J＝13.2,5.1Hz,1H),4.58–4.35(m,5H),3.42–3.37(m,3H),3.16–3.02(m,2H),2.99–2.87(m,2H),2.66–2.57(m,1H),2.46–2.37(m,1H),2.20–2.08(m,5H),2.06–1.98(m,1H),1.89–1.81(m,2H),1.22(d,J＝6.0Hz,6H),1.14(d,J＝6.8Hz,6H).LCMS(ESI)m/z:C 42 H 49 ClN 7 O 6 S + [M+H] + Calculated 814.31, measured 814.3.
Example 36: preparation of 3- (5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-02974)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-02974) (white solid, 8.4mg, yield 49%) was prepared using (R) -3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-2-amine (CAS number: 877399-52-5) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ8.01(s,1H),7.92(d,J＝7.9Hz,1H),7.88(s,1H),7.76(d,J＝7.7Hz,1H),7.65(d,J＝7.3Hz,2H),7.51(dd,J＝9.0,4.8Hz,1H),7.29(t,J＝8.6Hz,1H),7.15(s,1H),6.35(q,J＝6.5Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.61–4.56(m,2H),4.55(s,2H),3.69–3.61(m,2H),3.42–3.33(m,2H),2.97–2.87(m,1H),2.84–2.75(m,1H),2.59–2.47(m,1H),2.46–2.32(m,4H),2.24–2.14(m,1H),1.95(d,J＝6.6Hz,3H).LCMS(ESI)m/z:C 35 H 35 Cl 2 FN 7 O 4 + [M+H] + Calculated 706.21, measured 706.2.
Example 37: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03014)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03014) (white solid, 5mg, yield 28%) was prepared using 2- ((2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-10) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 25. 1 H NMR(400MHz,MeOD)δ8.01(s,1H),7.93(d,J＝7.8Hz,1H),7.89(s,1H),7.77(d,J＝7.8Hz,1H),7.71(d,J＝7.7Hz,1H),7.57(d,J＝3.8Hz,2H),7.38–7.31(m,1H),7.18(d,J＝8.6Hz,1H),6.76(d,J＝2.4Hz,1H),6.65(dd,J＝8.7,2.5Hz,1H),6.47(s,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.66–4.52(m,4H),3.85(s,3H),3.60–3.31(m,8H),2.98–2.89(m,1H),2.88(s,3H),2.84–2.75(m,1H),2.53(qd,J＝13.2,4.7Hz,1H),2.24–2.14(m,1H).LCMS(ESI)m/z:C 39 H 40 F 3 N 8 O 5 + [M+H] + Calculated 757.31, found 757.3.
Example 38: preparation of 3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03015)
Referring to scheme 11, step 2 and the procedure of example 1, (2- ((2- ((4- (4-aminopiperidin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared using the procedure of reference scheme 3 and intermediate example 9 gave the title compound (GT-03015) (white solid, 5mg, 30% yield). 1 H NMR(400MHz,MeOD)δ11.75(s,1H),11.00(s,1H),9.45(s,2H),8.43(s,1H),8.20(s,1H),7.87–7.80(m,2H),7.75(d,J＝7.8Hz,1H),7.61(dd,J＝13.8,7.6Hz,1H),7.51–7.36(m,2H),7.22(t,J＝7.3Hz,1H),6.93–6.79(m,1H),6.76–6.59(m,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.51(d,J＝17.7Hz,1H),4.43–4.29(m,3H),3.89–3.82(m,2H),3.80(s,3H),3.08–2.84(m,4H),2.65–2.59(m,1H),2.30–2.20(m,2H),2.07–1.84(m,3H),1.81(s,3H),1.77(s,3H),1.32–1.20(m,1H).LCMS(ESI)m/z:C 38 H 43 ClN 8 O 5 P + [M+H] + Calculated 757.28, found 757.3.
Example 39: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03113)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03113) (white solid, 5mg, 33% yield) was prepared using 2- ((2- ((4- (4-aminopiperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-11) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared in intermediate example 26. 1 H NMR(400MHz,MeOD)δ8.02(s,1H),7.90(d,J＝7.9Hz,1H),7.83(s,1H),7.73(d,J＝7.0Hz,2H),7.60(d,J＝3.2Hz,2H),7.40–7.34(m,1H),7.21(d,J＝8.6Hz,1H),6.96(s,1H),6.84(d,J＝8.0Hz,1H),6.49(s,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.65–4.56(m,2H),4.46(s,2H),3.99–3.90(m,3H),3.88(s,3H),3.62–3.46(m,1H),3.19–3.08(m,2H),2.98–2.91(m,1H),2.89(s,3H),2.83–2.75(m,1H),2.53(qd,J＝13.2,4.7Hz,2H),2.25–2.15(m,2H),2.09–1.93(m,2H).LCMS(ESI)m/z:C 40 H 42 F 3 N 8 O 5 + [M+H] + Calculated 771.32, measured 771.2.
Example 40: preparation of 3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03214)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03214) was prepared using 4,4' - (1- (4- (2-aminoethoxy) phenyl) but-1-ene-1, 2-diyl) diphenol (CAS number: 1946764-65-3) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione) (white solid, 5mg, 17% yield). 1 H NMR(500MHz,DMSO)δ11.01(s,1H),9.23(d,J＝1.5Hz,1H),7.80(s,3H),7.09(d,J＝8.8Hz,1H),6.95(dd,J＝15.4,8.6Hz,2H),6.90–6.83(m,2H),6.74(t,J＝7.1Hz,2H),6.66(d,J＝9.0Hz,1H),6.61–6.49(m,3H),6.42(d,J＝8.7Hz,1H),5.14(d,J＝13.4Hz,1H),4.46(s,1H),4.24(d,J＝127.4Hz,5H),3.27–3.15(m,2H),2.93(s,1H),2.60(s,1H),2.37–2.30(m,3H),2.03(s,1H),0.84(t,J＝7.4Hz,3H).LCMS(ESI)m/z:C 38 H 38 N 3 O 6 + [M+H] + Calculated 632.28, measured 632.3.
Example 41: preparation of N- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide (GT-03215)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03215) (white solid, 5mg, yield 25%) was prepared using N- (2-chloro-6-methylphenyl) -2- ((2-methyl-6- (piperazin-1-yl) pyrimidin-4-yl) amino) thiazole-5-carboxamide (CAS number: 910297-51-7) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ8.23(s,1H),7.94(d,J＝7.9Hz,1H),7.87(s,1H),7.75(d,J＝7.4Hz,1H),7.39–7.34(m,1H),7.28–7.24(m,2H),6.45(s,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.64–4.56(m,4H),3.97–3.83(m,2H),3.78–3.42(m,6H),2.94–2.87(m,1H),2.83–2.77(m,1H),2.62(s,3H),2.56–2.46(m,1H),2.31(s,3H),2.24–2.14(m,1H).LCMS(ESI)m/z:C 34 H 35 ClN 9 O 4 + [M+H] + Calculated 700.22, found 700.2.
Example 42: preparation of 3- (5- (((3S, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03264)
Referring to scheme 11, step 2 and the procedure of example 1, 1- ((3S, 4S) -3-fluoropiperidin-4-yl) -3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d is employed]Preparation of pyrimidine-4-amine and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the target Compound (GT-03264) (white)Coloured solid, 63.7mg, yield 18%). 1 H NMR(400MHz,MeOD)δ8.41(s,1H),7.93(d,J＝7.8Hz,1H),7.83(s,1H),7.74(d,J＝7.8Hz,1H),7.70–7.54(m,2H),7.43(t,J＝8.0Hz,2H),7.24–7.08(m,5H),5.50–5.25(m,2H),5.17(dd,J＝13.4,5.1Hz,1H),4.68–4.47(m,4H),3.94–3.81(m,1H),3.79–3.61(m,1H),3.57–3.33(m,2H),2.95–2.85(m,1H),2.82–2.72(m,1H),2.66–2.42(m,3H),2.23–2.13(m,1H).LCMS(ESI)m/z:C 34 H 35 ClN 9 O 4 + [M+H] + Calculated 661.27, measured 661.3.
Example 43: (E) Preparation of (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide (GT-03265)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03265) (white solid, 9.6mg, yield 57%) was prepared using (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (piperazin-1-yl) but-2-enamide (CAS number 2600734-22-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 HNMR(400MHz,MeOD)δ9.31–9.20(m,1H),8.75(s,1H),7.93(dd,J＝6.6,2.6Hz,1H),7.88(d,J＝7.8Hz,1H),7.80(s,1H),7.70(d,J＝7.8Hz,1H),7.67–7.62(m,1H),7.38(t,J＝8.9Hz,1H),7.33(s,1H),7.08–6.99(m,1H),6.80(d,J＝15.3Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.55(q,J＝17.3Hz,2H),4.34(s,2H),4.18(s,3H),3.88(s,2H),3.51–3.31(m,8H),2.98–2.86(m,1H),2.83–2.74(m,1H),2.51(qd,J＝13.2,4.6Hz,1H),2.22–2.13(m,1H).LCMS(ESI)m/z:C 37 H 37 ClFN 8 O 5 + [M+H] + Calculated 727.26, found 727.2.
Example 44: preparation of 2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03266)
Referring to scheme 11, procedure 2 and the procedure of example 1, 2- ((2-methoxy-4- (4- (piperazine-1-)) prepared using intermediate example 27Phenyl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-12) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03266) (white solid, 5mg, 33% yield). 1 H NMR(400MHz,MeOD)δ8.01(s,1H),7.90(d,J＝7.8Hz,1H),7.85(s,1H),7.79–7.69(m,2H),7.64–7.56(m,2H),7.42–7.31(m,1H),7.24–7.13(m,1H),6.88(s,1H),6.77(d,J＝7.5Hz,1H),6.48(s,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.57(q,J＝17.4Hz,2H),4.44(s,2H),4.01–3.91(m,2H),3.87(s,3H),3.78–3.38(m,8H),3.11–2.99(m,2H),2.97–2.90(m,1H),2.89(s,3H),2.84–2.73(m,1H),2.52(qd,J＝13.1,4.6Hz,1H),2.36–2.25(m,2H),2.24–2.12(m,1H),2.06–1.92(m,2H).LCMS(ESI)m/z:C 44 H 49 F 3 N 9 O 5 S + [M+H] + Calculated 840.38, measured 840.3.
Example 45: preparation of 2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide (GT-0396)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of intermediate example 3 was used to prepare (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f)][1,2,4]Triazolo [4,3-a ]][1,4]Diazepan-6-yl) -N- (2- (piperazin-1-yl) ethyl) acetamide and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-0396) (white solid, 5mg, 33% yield). 1 H NMR(400MHz,MeOD)δ7.89(d,J＝7.8Hz,1H),7.83(s,1H),7.71(d,J＝7.8Hz,1H),7.57–7.46(m,4H),5.17(dd,J＝13.2,5.0Hz,1H),4.56(q,J＝17.2Hz,2H),4.43(s,2H),3.85–3.46(m,13H),3.38(t,J＝5.6Hz,2H),2.95–2.75(m,5H),2.58–2.52(m,1H),2.49(s,3H),2.23–2.13(m,1H),1.72(s,3H).LCMS(ESI)m/z:C 39 H 43 ClN 9 O 4 S + [M+H] + Calculated 768.28, measured 768.3.
Example 46: preparation of 3- (5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03320)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03320) (white solid, 25mg, yield 26%) was prepared using 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine (CAS number 1801747-42-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ7.89(d,J＝7.9Hz,1H),7.82(s,1H),7.76–7.68(m,2H),7.60(s,1H),7.51–7.43(m,2H),5.18(dd,J＝13.3,5.1Hz,1H),4.62–4.47(m,4H),4.42(s,2H),3.29–3.22(m,2H),2.97–2.86(m,1H),2.84–2.75(m,1H),2.52(qd,J＝13.2,4.8Hz,1H),2.23–2.15(m,1H),2.14–2.02(m,4H),1.72(s,3H).LCMS(ESI)m/z:C 30 H 32 Cl 2 N 7 O 3 + [M+H] + Calculated 608.19, measured 608.3.
Example 47: preparation of 3- (5- ((((3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03321)
Referring to scheme 11, step 2 and the procedure of example 1, use is made of (3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Deck-4-amine (CAS number 1801765-04-7) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03321) (white solid, 5mg, yield 28%). 1 H NMR(400MHz,MeOD)δ7.89–7.84(m,1H),7.81(s,1H),7.73(d,J＝7.8Hz,1H),7.67–7.56(m,3H),6.15(dd,J＝13.7,6.5Hz,1H),5.17(dd,J＝13.3,5.2Hz,1H),4.14(d,J＝9.3Hz,1H),4.00(d,J＝9.3Hz,1H),3.88(d,J＝9.2Hz,1H),3.81–3.67(m,2H),3.51–3.41(m,2H),3.27–3.22(m,1H),3.14–3.00(m,2H),2.96–2.86(m,1H),2.84–2.73(m,1H),2.59–2.41(m,1H),2.22–2.11(m,1H),1.90–1.76(m,3H),1.72–1.62(m,1H).LCMS(ESI)m/z:C 32 H 37 ClN 9 O 4 S + [M+H] + Calculated 678.24, measured 678.2.
Example 48: preparation of 3- (5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03322)
Referring to scheme 11, procedure 2 and example 1, 1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3, 4-b) is employed]Pyrazin-6-yl) -4-methylpiperidin-4-amine (CAS number: 2160546-07-47) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the objective compound (GT-03322) (white solid, 7.6mg, yield 21%). 1 H NMR(400MHz,MeOD)δ8.41(s,1H),7.90(d,J＝7.8Hz,1H),7.75(s,1H),7.67(dd,J＝8.0,1.6Hz,2H),7.57(dd,J＝7.7,1.5Hz,1H),7.43(t,J＝7.9Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.72–4.63(m,2H),4.55(q,J＝17.4Hz,2H),4.42(s,2H),3.38–3.33(m,2H),2.98–2.86(m,1H),2.83–2.74(m,1H),2.51(qd,J＝13.4,4.9Hz,1H),2.22–2.16(m,1H),2.14–1.97(m,4H),1.74(s,3H).LCMS(ESI)m/z:C 31 H 31 Cl 2 N 8 O 3 + [M+H] + Calculated 633.19, measured 633.2.
Example 49: preparation of 3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03319)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03319) (white solid, 12.8mg, yield 27%) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (CAS number 2353496-90-7) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ8.41(s,1H),7.90(d,J＝7.8Hz,1H),7.75(s,1H),7.67(dd,J＝8.0,1.6Hz,2H),7.57(dd,J＝7.7,1.5Hz,1H),7.43(t,J＝7.9Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.72–4.63(m,2H),4.55(q,J＝17.4Hz,2H),4.42(s,2H),3.38–3.33(m,2H),2.98–2.86(m,1H),2.83–2.74(m,1H),2.51(qd,J＝13.4,4.9Hz,1H),2.22–2.16(m,1H),2.14–1.97(m,4H),1.74(s,3H).LCMS(ESI)m/z:C 31 H 31 Cl 2 N 8 O 3 + [M+H] + Calculated 633.19, measured 633.2.
Example 50: preparation of 3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03323)
Referring to scheme 11, step 2 and the method of example 1, N was used 4 - (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4, 6-diamine (CAS number: 179552-75-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03323) (white solid, 9.2mg, yield 21%). 1 H NMR(400MHz,MeOD)δ8.91(s,1H),8.54(s,1H),7.90–7.81(m,1H),7.80–7.71(m,1H),7.65–7.44(m,3H),7.41–7.25(m,1H),7.15(d,J＝16.5Hz,1H),5.17–5.07(m,1H),4.78(s,3H),4.51–4.39(m,2H),4.16(s,1H),3.98(s,1H),2.95–2.84(m,1H),2.82–2.72(m,1H),2.53–2.38(m,1H),2.21–2.10(m,1H).LCMS(ESI)m/z:C 29 H 25 ClFN 6 O 4 + [M+H] + Calculated 575.16, measured 575.2.
Example 51: preparation of 3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03324)
Referring to the procedure of scheme 12, the title compound (GT-03324) was prepared using 4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-ol (CAS number: 184775-71-6) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (white solid, 7.6mg, yield 19%). 1 H NMR(400MHz,MeOD)δ8.74(s,1H),8.14(s,1H),7.96(dd,J＝6.6,2.5Hz,1H),7.87(d,J＝7.8Hz,1H),7.78(s,1H),7.72–7.64(m,2H),7.37(t,J＝8.9Hz,1H),7.28(s,1H),5.47(s,2H),5.18(dd,J＝13.3,5.1Hz,1H),4.61–4.48(m,2H),4.12(s,3H),2.99–2.86(m,1H),2.84–2.75(m,1H),2.51(qd,J＝13.1,4.6Hz,1H),2.26–2.14(m,1H).LCMS(ESI)m/z:C 29 H 24 ClFN 5 O 5 + [M+H] + Calculated 576.14, measured 576.1.
Example 52: preparation of 3- (5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03325)
Referring to the procedure of scheme 12, the title compound (GT-03324) was prepared using 4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-ol (CAS number: 612501-52-7) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (white solid, 5mg, 13% yield). 1 H NMR(400MHz,MeOD)δ8.63(s,1H),8.04(s,1H),7.90–7.85(m,1H),7.78(s,1H),7.70(d,J＝7.5Hz,1H),7.56–7.51(m,2H),7.30–7.26(m,2H),5.46(s,2H),5.18(dd,J＝13.2,5.1Hz,1H),4.59–4.53(m,2H),4.11(s,3H),2.93–2.88(m,1H),2.82–2.78(m,1H),2.54–2.47(m,1H),2.22–2.18(m,1H).LCMS(ESI)m/z:C 29 H 24 ClFN 5 O 5 + [M+H] + Calculated 576.14, measured 576.1.
Example 53: preparation of N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide (GT-03242)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03142) (white solid, 50mg, yield 54%) was prepared using N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) piperidine-4-carboxamide (CAS number: 345627-80-7) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234). 1 HNMR(400MHz,DMSO)δ12.44(s,1H),11.01(s,1H),10.74(s,1H),7.87(s,1H),7.82(t,J＝6.3Hz,1H),7.75(d,J＝7.9Hz,1H),7.40(s,1H),6.71(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.55–4.46(m,2H),4.46–4.33(m,3H),4.05(s,2H),3.44–3.38(m,2H),3.16–3.08(m,1H),2.79–2.70(m,1H),2.65–2.57(m,1H),2.45–2.37(m,1H),2.16–2.07(m,1H),2.04–1.97(m,4H),1.17(s,9H).LCMS(ESI)m/z:C 31 H 37 N 6 O 5 S 2 + [M+H] + Calculated 637.23, measured 637.3.
Example 54: preparation of N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide (GT-03397)
Reference scheme 11 step 2And the title compound (GT-03397) (white solid, 19mg, yield 34.6%) was obtained by the method of example 1. 1 H NMR(400MHz,DMSO)δ11.00(s,1H),9.21(s,1H),8.14(ddt,J＝25.0,23.7,12.0Hz,2H),7.93(dd,J＝5.2,3.8Hz,2H),7.85–7.41(m,4H),5.13(dd,J＝13.3,5.2Hz,1H),4.42(dd,J＝51.1,17.6Hz,2H),3.60(d,J＝40.1Hz,8H),3.17(s,6H),2.95–2.88(m,1H),2.61(d,J＝16.6Hz,1H),2.44–2.31(m,1H),2.07–1.96(m,1H).LCMS(ESI)C 33 H 32 N 5 O 7 + [M+H] + Calculated 610.23, found 610.3.
Example 55: preparation of 8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03409)
Referring to scheme 11, step 2 and the procedure of example 1, 9-ethyl-6, 6-dimethyl-11-oxo-8- (piperazin-1-yl) -6, 11-dihydro-5H-benzo [ b ] prepared in intermediate example 44 was used]Carbazole-3-carbonitrile (GT-D-42) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03409) (white solid, 48mg, yield 55.5%). 1 H NMR(400MHz,MeOD)δ8.40(d,J＝8.3Hz,1H),8.23(s,1H),7.95(d,J＝7.9Hz,1H),7.84(d,J＝12.9Hz,2H),7.76(t,J＝7.8Hz,1H),7.60–7.49(m,1H),7.42(s,1H),5.19(dd,J＝13.2,5.0Hz,1H),4.65–4.40(m,4H),3.40(d,J＝63.5Hz,8H),2.98–2.75(m,4H),2.52(dd,J＝12.9,4.5Hz,1H),2.20(d,J＝10.3Hz,1H),1.80(s,6H),1.35(t,J＝7.5Hz,3H).LCMS(ESI)C 39 H 39 N 6 O 4 + [M+H] + Calculated 655.30, measured 655.3.
Example 56: preparation of 3- (5- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (GT-03410)
Referring to scheme 11, step 2 and the procedure of example 1, the 5, 7-dimethoxy-2- (4- (piperazin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-51) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared in intermediate example 61 were used to prepare the title compound (GT-03410) (whiteColor solid, 48mg, yield 53.5%). 1 H NMR(400MHz,DMSO)δ11.02(s,2H),8.13(d,J＝9.0Hz,2H),7.86(d,J＝8.3Hz,2H),7.76(d,J＝7.8Hz,1H),7.11(d,J＝9.1Hz,2H),6.79(s,1H),6.55(s,1H),5.16(dd,J＝13.2,4.9Hz,1H),4.48(dt,J＝40.8,12.5Hz,4H),4.09(d,J＝9.9Hz,2H),3.88(d,J＝13.9Hz,6H),3.20(s,6H),2.93(dd,J＝22.0,8.5Hz,1H),2.68–2.60(m,1H),2.44(dd,J＝12.9,4.1Hz,1H),2.04(d,J＝5.6Hz,1H).LCMS(ESI)C 34 H 35 N 6 O 6 + [M+H] + Calculated 623.26, measured 623.3.
Example 57: preparation of N- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide (GT-03411)
Referring to scheme 11, step 2 and the procedure of example 1, N- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide (CAS number 2600734-25-4) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) was used to prepare the title compound (GT-03411) (white solid, 34mg, 40.5% yield). 1 H NMR(400MHz,MeOD)δ9.05(s,1H),8.66(s,1H),7.84(dd,J＝6.6,2.5Hz,1H),7.74(d,J＝7.9Hz,1H),7.54(dd,J＝17.3,11.2Hz,3H),7.27(dd,J＝16.5,7.6Hz,2H),6.65(dd,J＝16.8,10.3Hz,1H),6.41(d,J＝16.8Hz,1H),5.80(d,J＝11.6Hz,1H),5.07(dd,J＝13.1,5.0Hz,1H),4.59–4.32(m,4H),3.93(s,2H),2.93(d,J＝83.9Hz,11H),2.69(d,J＝14.1Hz,1H),2.46–2.22(m,3H),2.10(s,1H).LCMS(ESI)C 38 H 39 ClFN 8 O 5 + [M+H] + Calculated 741.27, measured 741.3.
Example 58: preparation of 3- (5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03412)
Prepared by the method of step 2 and example 1, reference scheme 11, using N- (3, 4-dichloro-2-fluorophenyl) -7-methoxy-6- (piperidin-4-yloxy) quinazolin-4-amine (CAS number 1429809-12-0) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dioneTo the target compound (GT-03412) (white solid, 47mg, yield 56.5%). 1 H NMR(400MHz,MeOD)δ8.58(s,1H),8.08(s,1H),7.84(d,J＝7.9Hz,1H),7.76(s,1H),7.66(s,1H),7.50–7.37(m,2H),7.19(s,1H),5.13–5.08(m,1H),4.55–4.39(m,4H),3.99(d,J＝13.6Hz,3H),3.31(d,J＝57.2Hz,6H),2.78(ddd,J＝41.1,25.9,14.3Hz,2H),2.47–2.07(m,5H).LCMS(ESI)C 34 H 32 Cl 2 FN 6 O 5 + [M+H] + Calculated 693.18, measured 693.2.
Example 59: preparation of N- (5- (3, 5-Dimethoxyphenylethyl) -1H-pyrazol-3-yl) -4- ((3R, 5S) -4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) benzamide (GT-03447)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03447) (white solid, 26mg, yield 52.9%) was prepared using N- (5- (3, 5-dimethoxyphenethyl) -1H-pyrazol-3-yl) -4- ((3R, 5S) -3, 5-dimethylpiperazin-1-yl) benzamide (CAS number: 1615687-07-4) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ8.22–7.50(m,6H),7.23–6.94(m,2H),6.34(dd,J＝18.8,2.0Hz,3H),5.17(dd,J＝13.3,5.1Hz,1H),4.74–4.39(m,4H),4.08(d,J＝12.2Hz,2H),3.73(s,6H),3.56(dd,J＝35.7,17.8Hz,2H),3.15(s,1H),3.06–2.72(m,7H),2.56–2.42(m,1H),2.24–2.11(m,1H),1.68(s,5H),1.46–1.33(m,1H).LCMS(ESI)C 40 H 46 N 7 O 6 + [M+H] + Calculated 720.35, found 720.4.
Example 60: preparation of 3- (1-oxo-5- ((4- (4- (3- (quinolin-4-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-03441)
Referring to scheme 11, procedure 2 and example 1, 4- (6- (4- (piperazin-1-yl) phenyl) pyrazolo [1,5-a ] is employed]Pyrimidin-3-yl) quinoline (CAS number: 1062368-24-4) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the objective compound (GT-03441) (white solid, 38mg, yield 60.4%) 。 1 H NMR(400MHz,MeOD)δ9.29(d,J＝2.2Hz,1H),9.04(d,J＝2.2Hz,1H),8.97(d,J＝5.9Hz,1H),8.79(s,1H),8.62(d,J＝8.8Hz,1H),8.45(d,J＝5.9Hz,1H),8.14(d,J＝8.6Hz,1H),8.06(t,J＝7.7Hz,1H),7.87(t,J＝7.8Hz,2H),7.74(d,J＝16.1Hz,1H),7.72–7.59(m,3H),7.13(d,J＝8.8Hz,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.56–4.44(m,4H),3.78–3.23(m,8H),2.86–2.67(m,2H),2.44(dt,J＝13.1,8.5Hz,1H),2.12(dd,J＝14.8,9.8Hz,1H).LCMS(ESI)C 39 H 35 N 8 O 3 + [M+H] + Calculated 663.28, measured 663.3.
Example 61: preparation of 3- (1-oxo-5- ((4- (4- (3- (quinolin-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione (GT-03442)
Referring to scheme 11, procedure 2 and example 1,5- (6- (4- (piperazin-1-yl) phenyl) pyrazolo [1,5-a ] is employed]Pyrimidin-3-yl) quinoline (CAS number: 1432597-26-6) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the title compound (GT-03442) (white solid, 40mg, yield 58.4%). 1 H NMR(400MHz,MeOD)δ9.15(d,J＝2.2Hz,1H),8.98(s,1H),8.80(d,J＝2.3Hz,2H),8.42(s,1H),8.08(d,J＝8.5Hz,1H),8.00(dd,J＝17.4,8.7Hz,2H),7.87(d,J＝8.0Hz,1H),7.71(d,J＝7.8Hz,3H),7.66(s,1H),7.64(s,1H),7.11(d,J＝8.9Hz,2H),5.10–5.08(m,1H),4.49(s,4H),3.33(d,J＝40.3Hz,8H),2.82–2.77(m,1H),2.74–2.70(m,1H),2.42(s,1H),2.10(s,1H).LCMS(ESI)C 39 H 35 N 8 O 3 + [M+H] + Calculated 663.28, measured 663.3.
Example 62: preparation of 4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide (GT-03448)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03448) was prepared using 4- (2, 6-dichlorobenzoylamino) -N- (piperidin-4-yl) -1H-pyrazole-3-carboxamide (CAS number: 844442-38-2) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (white solid, 33mg, 62.7% yield). 1 H NMR(400MHz,MeOD)δ8.34(s,1H),7.91(d,J＝7.9Hz,1H),7.77(s,1H),7.69(d,J＝7.9Hz,1H),7.54–7.40(m,3H),5.17(dd,J＝13.4,5.1Hz,1H),4.64–4.40(m,4H),4.11(t,J＝57.7Hz,1H),3.70–3.44(m,2H),3.26–3.11(m,2H),2.86(dtd,J＝15.6,13.3,3.9Hz,2H),2.51(qd,J＝13.4,4.9Hz,1H),2.18(d,J＝10.4Hz,4H),1.92(d,J＝10.0Hz,1H).LCMS(ESI)C 30 H 30 Cl 2 N 7 O 5 + [M+H] + Calculated 638.17, found 638.2.
Example 63: preparation of 3- (5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03485)
The title compound (GT-03485) (white solid, 44mg, yield 57.9%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ9.13(s,1H),7.87–7.78(m,4H),7.68(d,J＝8.2Hz,1H),6.54(s,1H),5.12–5.07(m,1H),4.60–4.44(m,4H),4.17(s,1H),3.84(s,2H),3.71–3.31(m,11H),3.30(s,3H),2.88–2.77(m,1H),2.70(d,J＝15.5Hz,1H),2.51–2.36(m,1H),2.15–2.05(m,1H),1.96–1.86(m,2H),1.67(d,J＝6.6Hz,2H),1.43(d,J＝6.6Hz,6H).LCMS(ESI)C 37 H 46 N 11 O 4 + [M+H] + Calculated 708.37, measured 708.4.
Example 64: preparation of 6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03693)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03693) (white solid, 45mg, yield 52.31%) was prepared using 2- (4-phenoxyphenyl) -6- (piperidin-4-yl) nicotinamide (GT-D-66) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared by intermediate example 50. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.50(s,1H),7.93(s,1H),7.88(s,1H),7.83–7.77(m,3H),7.72(d,J＝8.7Hz,2H),7.52(s,1H),7.45–7.40(m,2H),7.29(d,J＝7.9Hz,1H),7.18(t,J＝7.4Hz,1H),7.05(dd,J＝12.2,8.2Hz,4H),5.14(dd,J＝13.2,5.1Hz,1H),4.45(dt,J＝38.1,17.6Hz,5H),3.46(d,J＝10.9Hz,2H),3.11–2.98(m,3H),2.97–2.88(m,1H),2.64–2.57(m,1H),2.46–2.38(m,1H),2.27–2.17(m,2H),2.12–2.05(m,2H),2.02(dd,J＝8.8,3.5Hz,1H).LCMS(ESI)C 37 H 36 N 5 O 5 + [M+H] + Calculated 630.26, measured 630.30.
Example 65: preparation of 1'- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -6- (4-phenoxyphenyl) -1',2',3',6 '-tetrahydro- [2,4' -bipyridine ] -5-carboxamide (GT-03552)
Referring to scheme 11, step 2 and the procedure of example 1, 6- (4-phenoxyphenyl) -1',2',3',6' -tetrahydro- [2,4' -bipyridine was used]The title compound (GT-03552) was prepared from-5-carboxamide (CAS number 2484693-14-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) (white solid, 73mg, 40% yield). 1 H NMR(400MHz,MeOD)δ7.97–7.90(m,2H),7.83(s,1H),7.78–7.72(m,3H),7.63(d,J＝8.1Hz,1H),7.43–7.34(m,2H),7.16(t,J＝7.5Hz,1H),7.08–6.98(m,4H),6.79(s,1H),5.20(dd,J＝13.4,5.1Hz,1H),4.67–4.52(m,4H),4.05–3.96(m,2H),3.91–3.77(m,1H),3.53–3.38(m,1H),3.25–3.10(m,1H),3.07–2.86(m,2H),2.84–2.72(m,1H),2.60–2.45(m,1H),2.24–2.13(m,1H).LCMS(ESI)C 37 H 34 N 5 O 5 + [M+H] + Calculated 628.26, measured 628.23.
Example 66: preparation of 6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03636)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03636) (white solid, 32mg, yield 34%) was prepared using 2- (4-phenoxyphenyl) -6- (piperazin-1-yl) nicotinamide (GT-D-76) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared by intermediate example 51. 1 H NMR(400MHz,MeOD)δ7.94(d,J＝7.8Hz,1H),7.85–7.79(m,2H),7.73(d,J＝7.9Hz,1H),7.70–7.65(m,2H),7.40–7.35(m,2H),7.15(t,J＝7.4Hz,1H),7.06–6.97(m,4H),6.91(d,J＝8.7Hz,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.61–4.51(m,4H),3.72–3.32(m,8H),2.98–2.87(m,1H),2.84–2.75(m,1H),2.52(qd,J＝13.1,4.4Hz,1H),2.25–2.12(m,1H).LCMS(ESI)m/z:C 36 H 35 N 6 O 5 + [M+H] + Calculated 631.27; found 631.3.
Example 67: preparation of 6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03803)
Referring to scheme 11, step 2 and the procedure of example 1, the 6- (4- (methylamino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-D-77) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared by intermediate example 52 gave the title compound (GT-03803) (white solid, 60mg, yield 68%). 1 H NMR(400MHz,MeOD)δ7.91(d,J＝7.8Hz,1H),7.87(d,J＝8.9Hz,1H),7.83(s,1H),7.72(d,J＝7.9Hz,1H),7.69–7.64(m,2H),7.42–7.36(m,2H),7.19–7.14(m,1H),7.08–7.00(m,5H),5.18(dd,J＝13.3,5.1Hz,1H),4.78–4.65(m,3H),4.57(q,J＝17.8Hz,2H),4.37(d,J＝13.0Hz,1H),3.80–3.70(m,1H),3.19–3.06(m,2H),2.97–2.86(m,1H),2.83–2.78(m,1H),2.77(s,3H),2.51(qd,J＝13.2,4.6Hz,1H),2.36–2.26(m,2H),2.23–2.14(m,1H),2.04–1.88(m,2H).LCMS(ESI)m/z:C 38 H 39 N 6 O 5 + [M+H] + Calculated 659.30; found 659.3.
Example 68: preparation of 6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03824)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03824) was prepared using 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) and 2- (4-phenoxyphenyl) -6- (piperidin-4-yl) nicotinamide (GT-D-66) prepared according to intermediate example 50 (white solid, 48mg, yield 57%). 1 H NMR(400MHz,DMSO)δ11.07(s,1H),10.82(s,1H),9.42(s,1H),8.83(d,J＝7.9Hz,1H),8.43(s,1H),8.29(s,1H),7.98(d,J＝7.6Hz,1H),7.85(d,J＝7.4Hz,1H),7.66(t,J＝7.6Hz,1H),7.13(t,J＝53.6Hz,1H),6.91(d,J＝8.0Hz,1H),5.20(dd,J＝13.1,5.1Hz,1H),4.56–4.50(m,2H),4.42(s,2H),3.89–3.67(m,10H),3.57–3.54(m,1H),3.25(d,J＝10.6Hz,2H),3.02–2.91(m,1H),2.72–2.63(m,1H),2.40–2.23(m,5H),2.12–2.03(m,1H).LCMS(ESI)m/z:C 34 H 37 F 2 N 10 O 5 + [M+H] + Calculated 703.29; found 703.3.
Example 69: preparation of 6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03825)
The title compound (GT-03825) (white solid, 54mg, 60% yield) was prepared according to the procedure for example 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.83(s,1H),8.04(d,J＝6.0Hz,1H),7.70–7.62(m,4H),7.55(s,1H),7.46–7.39(m,2H),7.24(s,1H),7.18(t,J＝7.4Hz,1H),7.07(dd,J＝8.6,1.0Hz,2H),7.04–6.99(m,2H),6.90(d,J＝8.8Hz,1H),5.14(dd,J＝13.1,4.8Hz,1H),4.71–4.57(m,3H),4.55–4.33(m,3H),3.68–3.53(m,1H),3.00–2.83(m,3H),2.70–2.57(m,4H),2.47–2.36(m,1H),2.31(d,J＝13.1Hz,1H),2.20(d,J＝10.9Hz,1H),2.07–1.97(m,1H),1.84–1.68(m,2H).LCMS(ESI)m/z:C 38 H 38 FN 6 O 5 + [M+H] + Calculated 677.29; found 677.3.
Example 70: preparation of 6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03826)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03826) (white solid, 61mg, yield 68%) was prepared using 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) and 2- (4-phenoxyphenyl) -6- (piperidin-4-yl) nicotinamide (GT-D-66) prepared according to intermediate example 50, 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.68(s,1H),7.72–7.62(m,5H),7.54(s,1H),7.46–7.40(m,2H),7.23(s,1H),7.20–7.16(m,1H),7.10–7.05(m,2H),7.04–6.99(m,2H),6.89(d,J＝8.8Hz,1H),5.10(dd,J＝13.1,5.1Hz,1H),4.70–4.55(m,3H),4.54–4.47(m,1H),4.45–4.27(m,2H),3.64–3.51(m,1H),2.98–2.84(m,3H),2.65–2.56(m,4H),2.46–2.35(m,1H),2.29–2.16(m,2H),2.05–1.96(m,1H),1.83–1.64(m,2H).LCMS(ESI)m/z:C 38 H 38 FN 6 O 5 + [M+H] + Calculated 677.29; found 677.3.
Example 71: preparation of 6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03830)
The title compound (GT-03830) was prepared according to the procedure for scheme 11 and example 1 (white solid, 55mg, 63% yield). 1 H NMR(400MHz,DMSO)δ11.05(s,1H),10.45(s,1H),7.95–7.81(m,2H),7.69–7.61(m,4H),7.52(s,1H),7.43(t,J＝7.7Hz,2H),7.23(s,1H),7.18(t,J＝7.1Hz,1H),7.07(d,J＝8.6Hz,2H),7.02(d,J＝8.6Hz,2H),6.90(d,J＝8.8Hz,1H),5.19(dd,J＝13.2,4.8Hz,1H),4.73–4.43(m,5H),4.26–4.11(m,1H),3.00–2.87(m,4H),2.72–2.61(m,5H),2.44–2.31(m,2H),2.30–2.18(m,2H),2.07–1.97(m,1H),1.89–1.69(m,2H).LCMS(ESI)m/z:C 38 H 39 N 6 O 5 + [M+H] + Calculated 659.30; found 659.3.
Example 72: preparation of 6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03748)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03748) (white solid, 43mg, yield 65%) was obtained using 2- (4-phenoxyphenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) nicotinamide (GT-D-78) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 53. 1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.87–7.68(m,3H),7.67–7.60(m,3H),7.53(s,1H),7.46–7.38(m,2H),7.27–7.14(m,2H),7.07(d,J＝7.8Hz,2H),7.01(d,J＝8.6Hz,2H),6.88(d,J＝8.8Hz,1H),5.13(dd,J＝13.2,5.0Hz,1H),4.58(d,J＝12.6Hz,2H),4.49(d,J＝17.5Hz,1H),4.36(d,J＝17.3Hz,1H),3.88–3.55(m,10H),2.99–2.82(m,3H),2.70–2.57(m,1H),2.45–2.31(m,1H),2.22–2.08(m,2H),2.05–1.95(m,1H),1.70–1.54(m,2H).LCMS(ESI)m/z:C 41 H 44 N 7 O 5 + [M+H] + Calculated 714.34; actual measurement 714.3.
Example 73: preparation of 6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03749)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03750) (white solid, 41mg, 60% yield) was prepared using 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) and 2- (4-phenoxyphenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) nicotinamide (GT-D-78) prepared according to intermediate example 53. 1 HNMR(400MHz,MeOD)δ7.86(d,J＝9.0Hz,1H),7.72–7.62(m,4H),7.42–7.35(m,2H),7.17(t,J＝7.3Hz,1H),7.08–6.96(m,5H),5.20–5.10(m,2H),4.68–4.50(m,4H),4.08–3.96(m,2H),3.82–3.32(m,8H),3.14–3.02(m,2H),2.95–2.87(m,1H),2.82–2.76(m,1H),2.59–2.44(m,1H),2.33–2.13(m,3H),1.90–1.68(m,2H).LCMS(ESI)m/z:C 41 H 43 FN 7 O 5 + [M+H] + Calculated 732.33; found 732.4.
Example 74: preparation of 6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03750)
The title compound (GT-03750) (white solid, 40mg, 59% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ7.91(d,J＝9.0Hz,1H),7.83(d,J＝5.9Hz,1H),7.65(d,J＝8.7Hz,2H),7.59(d,J＝8.6Hz,1H),7.43–7.35(m,2H),7.17(t,J＝7.4Hz,1H),7.10–7.01(m,5H),5.16(dd,J＝13.3,5.1Hz,1H),4.94–4.88(m,1H),4.66–4.44(m,4H),4.22(s,2H),3.70–3.32(m,8H),3.19–3.10(m,2H),2.96–2.86(m,1H),2.82–2.73(m,1H),2.50(qd,J＝13.2,4.7Hz,1H),2.34–2.24(m,2H),2.22–2.14(m,1H),1.93–1.77(m,2H).LCMS(ESI)m/z:C 41 H 43 FN 7 O 5 + [M+H] + Calculated 732.33; found 732.3.
Example 75: preparation of 6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03751)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03751) was prepared using 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) and 2- (4-phenoxyphenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) nicotinamide (GT-D-78) prepared according to intermediate example 53 (GT-03751) (white solid, 35mg, 51% yield). 1 HNMR(400MHz,MeOD)δ7.91(d,J＝9.0Hz,1H),7.68–7.61(m,2H),7.54(s,1H),7.44–7.35(m,3H),7.17(t,J＝7.4Hz,1H),7.12–7.02(m,5H),5.13(dd,J＝13.3,5.2Hz,1H),4.94–4.87(m,1H),4.64–4.46(m,4H),4.15(s,2H),3.87–3.32(m,8H),3.21–3.10(m,3H),2.97–2.85(m,1H),2.82–2.72(m,1H),2.49(qd,J＝13.2,4.7Hz,1H),2.33–2.26(m,2H),2.23–2.12(m,1H),1.92–1.79(m,2H).LCMS(ESI)m/z:C 41 H 43 FN 7 O 5 + [M+H] + Calculated 732.33; found 732.4.
Example 76: preparation of 6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03755)
The title compound (GT-03755) (white solid, 31mg, 46% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ7.91(d,J＝9.0Hz,1H),7.84(d,J＝7.5Hz,1H),7.75(d,J＝7.5Hz,1H),7.68–7.63(m,2H),7.59(t,J＝7.6Hz,1H),7.43–7.36(m,2H),7.21–7.14(m,1H),7.13–7.01(m,5H),5.19(dd,J＝13.3,5.2Hz,1H),4.81–4.57(m,4H),4.26–3.99(m,2H),3.72–3.32(m,7H),3.30–3.06(m,4H),3.00–2.87(m,1H),2.84–2.73(m,1H),2.55(qd,J＝13.3,4.7Hz,1H),2.36–2.26(m,2H),2.24–2.16(m,1H),1.92–1.77(m,2H).LCMS(ESI)m/z:C 41 H 44 N 7 O 5 + [M+H] + Calculated 714.34; actual measurement 714.3.
Example 77: preparation of 3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03472)
Referring to scheme 11 and the procedure of example 1, 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) and 3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-d ] prepared according to intermediate example 2 were used]Pyrimidine-4-amine hydrochloride was prepared to give the title compound (GT-03472) (white solid, 5mg, yield 25%). 1 HNMR(400MHz,MeOD)δ8.42(s,1H),7.90–7.83(m,1H),7.78(d,J＝7.7Hz,1H),7.67(d,J＝7.9Hz,2H),7.42(t,J＝7.9Hz,2H),7.23–7.08(m,5H),5.28–5.11(m,2H),4.66–4.63(m,2H),3.85–3.78(m,2H),3.57–3.43(m,2H),2.97–2.74(m,2H),2.69–2.50(m,3H),2.44–2.14(m,3H).LCMS(ESI)C 36 H 34 FN 8 O 4 + [M+H] + Calculated 661.27, measured 661.3.
Example 78: preparation of 3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03605)
The title compound (GT-03605) (white solid, 34mg, 38% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ8.42(s,1H),7.92(d,J＝6.0Hz,1H),7.75–7.61(m,3H),7.42(t,J＝7.9Hz,2H),7.22–7.09(m,5H),5.26–5.13(m,2H),4.70–4.56(m,4H),3.84–3.72(m,2H),3.58–3.45(m,2H),2.97–2.35(m,8H).LCMS(ESI)m/z:C 36 H 34 FN 8 O 4 + [M+H] + Calculated 661.27; found 661.3.
Example 79: preparation of 3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03473)
Referring to scheme 11 and the procedure of example 1, 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) and 3- (4-phenoxyphenyl) -1- (piperidin-4-yl) -1H-pyrazolo [3,4-d ] prepared according to intermediate example 2 were used]Target compound (GT-034) prepared from pyrimidine-4-amine hydrochloride73 (white solid, 5mg, yield 27%). 1 HNMR(400MHz,MeOD)δ8.39(s,1H),7.73–7.62(m,3H),7.51(d,J＝9.7Hz,1H),7.42(t,J＝8.0Hz,2H),7.22–7.06(m,5H),5.30–5.19(m,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.66–4.51(m,4H),3.75–3.71(m,2H),3.50–3.37(m,2H),2.96–2.85(m,1H),2.84–2.75(m,1H),2.74–2.58(m,2H),2.57–2.47(m,1H),2.43–2.29(m,2H),2.25–2.14(m,1H).LCMS(ESI)C 36 H 34 FN 8 O 4 + [M+H] + Calculated 661.27, measured 661.3.
Example 80: preparation of 3- (4- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03641)
The title compound (GT-03641) was obtained by the method of step 2 of scheme 11 and example 1 (white solid, 51mg, yield 57%). 1 H NMR(400MHz,MeOD)δ8.43(s,1H),7.96(d,J＝7.4Hz,1H),7.91(d,J＝7.5Hz,1H),7.72(t,J＝7.6Hz,1H),7.69–7.63(m,2H),7.42(t,J＝7.8Hz,2H),7.23–7.13(m,3H),7.10(d,J＝7.9Hz,2H),5.30–5.19(m,2H),4.80–4.65(m,2H),4.56(s,2H),3.84–3.73(m,2H),3.58–3.44(m,2H),3.01–2.89(m,1H),2.86–2.77(m,1H),2.74–2.53(m,3H),2.48–2.33(m,2H),2.28–2.16(m,1H).LCMS(ESI)m/z:C 36 H 35 N 8 O 4 + [M+H] + Calculated 634.28; found 634.3.
Example 81: preparation of 3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03551)
The title compound (GT-03551) (white solid, 92mg, yield 52%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(500MHz,DMSO)δ11.26(d,J＝40.9Hz,1H),11.03(d,J＝3.7Hz,1H),9.23(s,1H),7.93–7.75(m,3H),7.04–6.84(m,5H),6.76–6.37(m,7H),5.15(dt,J＝13.1,5.4Hz,1H),4.56–4.45(m,3H),4.38(dd,J＝17.6,9.6Hz,1H),3.74(dd,J＝62.6,8.2Hz,2H),3.41–3.32(m,2H),3.10(ddd,J＝35.3,28.5,19.8Hz,4H),2.98–2.85(m,1H),2.59(t,J＝22.4Hz,1H),2.48–2.40(m,1H),2.39–2.28(m,2H),2.01(dd,J＝10.4,5.1Hz,1H),0.91–0.70(m,3H).LCMS(ESI)C 40 H 41 N 4 O 5 + [M+H] + Calculated 657.31, measured 657.3.
Example 82: preparation of 3- (5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03638)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03638) was prepared using 4,4' - (4-chloro-1- (4- (piperazin-1-yl) phenyl) but-1-en-1, 2-diyl) diphenol (GT-D-106) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 66 (GT-03638) (white solid, 31mg, 36% yield). 1 H NMR(500MHz,DMSO)δ11.02(t,J＝8.8Hz,2H),7.93–7.71(m,3H),7.16–6.84(m,5H),6.79–6.39(m,7H),5.20–5.08(m,1H),4.52(dd,J＝17.7,10.2Hz,3H),4.43–4.30(m,1H),3.90–3.76(m,1H),3.70(d,J＝12.2Hz,1H),3.43(dd,J＝14.5,7.3Hz,3H),3.29–2.86(m,6H),2.87–2.73(m,2H),2.61(d,J＝15.7Hz,1H),2.45–2.36(m,1H),2.01(dd,J＝10.7,5.0Hz,1H).LCMS(ESI)m/z:C 40 H 40 ClN 4 O 5 + [M+H] + Calculated 691.27; found 691.3.
Example 83: preparation of 3- (5- ((4- (4- (4-chloro-1, 2-diphenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03637)
Referring to scheme 11, step 2 and the procedure of example 1, 1- (4- (4-chloro-1, 2-diphenylbut-1-en-1-yl) phenyl) piperazine (GT-D-104) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 65 gave the title compound (GT-03637) (white solid, 50mg, yield 55%). 1 H NMR(400MHz,MeOD)δ7.92(d,J＝7.8Hz,1H),7.79(s,1H),7.70(d,J＝7.6Hz,1H),7.41–7.33(m,2H),7.32–7.25(m,3H),7.20–7.13(m,5H),6.81(d,J＝8.7Hz,2H),6.67(d,J＝8.8Hz,2H),5.18(dd,J＝13.3,5.1Hz,1H),4.59–4.54(m,2H),4.52(s,2H),3.77–3.67(m,2H),3.55–3.47(m,2H),3.39(t,J＝7.3Hz,2H),3.29–3.19(m,2H),3.04–2.94(m,2H),2.89(t,J＝7.3Hz,2H),2.83–2.75(m,1H),2.51(qd,J＝13.3,4.9Hz,1H),2.25–2.13(m,1H).LCMS(ESI)m/z:C 40 H 40 ClN 4 O 3 + [M+H] + Calculated 659.28; found 659.3.
Example 84: preparation of 3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03735)
Referring to the procedure of scheme 11 and example 1, 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) prepared in intermediate example 15 and 9-cyclopentyl-N prepared in intermediate example 47 were used 8 -phenyl-N 2 - (4- (piperazin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-62) gave the title compound (GT-03735) (white solid, 43mg, yield 57.94%). 1 H NMR(400MHz,DMSO)δ11.58(s,1H),11.03(s,1H),10.28(s,1H),10.10(s,1H),8.42(s,1H),8.02(t,J＝6.9Hz,1H),7.84(d,J＝8.0Hz,2H),7.71(d,J＝7.7Hz,1H),7.47(d,J＝8.8Hz,2H),7.39(t,J＝7.9Hz,2H),7.12(t,J＝7.4Hz,1H),7.03(d,J＝8.9Hz,2H),5.24–5.13(m,2H),4.64–4.56(m,3H),4.47(d,J＝17.6Hz,1H),3.83–3.75(m,3H),3.56–3.50(m,2H),3.24(ddd,J＝14.0,12.6,5.9Hz,3H),2.92(dd,J＝10.6,6.6Hz,1H),2.61(d,J＝17.3Hz,1H),2.44(dd,J＝13.1,4.3Hz,1H),2.33–2.24(m,2H),2.05(ddd,J＝12.7,9.5,4.3Hz,3H),1.92–1.84(m,2H),1.65–1.57(m,2H).LCMS(ESI)C 40 H 42 FN 10 O 3 + [M+H] + Calculated 729.33, measured 729.30.
Example 85: preparation of 3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03736)
The title compound (GT-03736) (white solid, 39mg, yield 52.55%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.55(s,1H),11.02(s,1H),10.20(s,1H),10.02(s,1H),8.42(s,1H),8.11(d,J＝6.0Hz,1H),7.83(d,J＝7.9Hz,2H),7.69(d,J＝8.5Hz,1H),7.47(d,J＝8.8Hz,2H),7.39(t,J＝7.9Hz,2H),7.12(t,J＝7.4Hz,1H),7.02(d,J＝8.9Hz,2H),5.17(td,J＝13.4,6.9Hz,2H),4.56–4.48(m,3H),4.38(d,J＝17.4Hz,1H),3.82–3.74(m,3H),3.53–3.48(m,2H),3.26(ddd,J＝20.5,9.2,5.4Hz,3H),2.92(dd,J＝10.6,6.8Hz,1H),2.61(d,J＝16.5Hz,1H),2.47–2.39(m,1H),2.29(dt,J＝15.7,8.1Hz,2H),2.10–2.00(m,3H),1.95–1.85(m,2H),1.62(dd,J＝12.8,6.6Hz,2H).LCMS(ESI)C 40 H 42 FN 10 O 3 + [M+H] + Calculated 729.33, measured 729.30.
Example 86: preparation of 3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03737)
Referring to the procedure of scheme 11 and example 1, 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared in intermediate example 16 and 9-cyclopentyl-N prepared in intermediate example 47 were used 8 -phenyl-N 2 - (4- (piperazin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-62) gave the title compound (GT-03737) (white solid, 40mg, yield 53.90%). 1 H NMR(400MHz,DMSO)δ11.79(s,1H),11.03(s,1H),10.26(s,1H),10.08(s,1H),8.42(s,1H),7.84(d,J＝8.0Hz,2H),7.74(d,J＝9.7Hz,2H),7.47(d,J＝8.9Hz,2H),7.39(t,J＝7.9Hz,2H),7.12(t,J＝7.4Hz,1H),7.02(d,J＝8.9Hz,2H),5.21(dd,J＝16.8,8.4Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.54(d,J＝17.7Hz,3H),4.41(d,J＝18.2Hz,1H),3.77(d,J＝4.9Hz,3H),3.43(d,J＝4.1Hz,2H),3.25–3.19(m,3H),2.96–2.88(m,1H),2.61(d,J＝16.4Hz,1H),2.44–2.36(m,1H),2.33–2.23(m,2H),2.04(ddd,J＝12.5,11.2,6.3Hz,3H),1.93–1.84(m,2H),1.62(dd,J＝12.6,6.4Hz,2H).LCMS(ESI)C 40 H 42 FN 10 O 3 + [M+H] + Calculated 729.33, measured 729.30.
Example 87: preparation of 3- (4- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03738)
The title compound (GT-03738) (white solid, 33mg,yield 45.59%). 1 H NMR(400MHz,DMSO)δ11.57(s,1H),11.07(s,1H),10.23(s,1H),10.05(s,1H),8.42(s,1H),8.07(d,J＝7.6Hz,1H),7.84(dd,J＝7.4,4.5Hz,3H),7.65(t,J＝7.6Hz,1H),7.47(d,J＝8.8Hz,2H),7.39(t,J＝7.9Hz,2H),7.12(t,J＝7.4Hz,1H),7.02(d,J＝8.9Hz,2H),5.23–5.15(m,2H),4.95(d,J＝17.7Hz,1H),4.52(dd,J＝26.4,15.8Hz,3H),3.78(d,J＝9.9Hz,2H),3.45(d,J＝18.1Hz,2H),3.35–3.23(m,4H),3.00–2.91(m,1H),2.69–2.61(m,1H),2.31(ddd,J＝29.0,14.6,6.1Hz,3H),2.10–2.01(m,3H),1.90(dd,J＝14.6,6.4Hz,2H),1.62(dd,J＝12.8,6.6Hz,2H).LCMS(ESI)C 40 H 43 N 10 O 3 + [M+H] + Calculated 711.34, measured 711.30.
Example 88: preparation of 2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide (GT-03477)
The title compound (GT-03477) (GT-03477) (white solid, 5mg, yield 6%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,MeOD)δ7.59(dd,J＝10.6,8.2Hz,1H),7.50(d,J＝4.8Hz,1H),7.19–7.12(m,2H),7.05–6.98(m,1H),6.97–6.89(m,1H),6.81(dd,J＝8.6,4.9Hz,2H),6.61(t,J＝7.8Hz,1H),6.58–6.52(m,1H),6.32(s,1H),5.51–5.39(m,1H),5.25–5.10(m,2H),4.69–4.62(m,3H),4.38–4.30(m,2H),2.97–2.86(m,1H),2.83–2.74(m,1H),2.49(dt,J＝13.1,8.5Hz,1H),2.22–2.11(m,1H).LCMS(ESI)C 33 H 28 FN 6 O 6 S + [M+H] + Calculated 655.18, found 655.2.
Example 89: preparation of 2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide (GT-03543)
Referring to scheme 11, procedure 2 and the procedure of example 1, using 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (piperazin-1-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-69) and 3- (5- (bromomethyl) -1-oxo-isoindolin-2-yl) piperidine prepared in intermediate example 41 The 2, 6-dione was prepared to give the target compound (GT-03543) (white solid, 35mg, yield 20%). 1 H NMR(400MHz,MeOD)δ7.95(d,J＝7.8Hz,1H),7.81(s,1H),7.74(d,J＝7.9Hz,1H),7.47–7.41(m,2H),7.38(d,J＝2.2Hz,1H),7.32(dd,J＝8.4,2.3Hz,1H),7.17(d,J＝3.7Hz,1H),7.07–7.00(m,1H),6.95(dd,J＝8.9,3.1Hz,1H),6.91–6.86(m,1H),6.45(s,1H),5.19(dd,J＝13.4,5.1Hz,1H),4.71–4.65(m,1H),4.60–4.56(m,3H),3.96–3.84(m,2H),3.68–3.53(m,2H),3.21–3.05(m,2H),2.96–2.87(m,1H),2.84–2.76(m,1H),2.52(qd,J＝13.2,4.8Hz,1H),2.25–2.15(m,1H).LCMS(ESI)C 37 H 35 FN 7 O 6 S + [M+H] + Calculated 724.23, measured 724.2.
Example 90: preparation of 2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide (GT-03745)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03745) was prepared using 2- (5-fluoro-2-hydroxyphenyl) -2- (6- (4- (methylamino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-70) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared in intermediate example 42 (white solid, 67mg, 40% yield). 1 H NMR(400MHz,MeOD)δ7.93(d,J＝7.9Hz,1H),7.85(s,1H),7.75(d,J＝7.9Hz,1H),7.69(s,1H),7.65–7.58(m,1H),7.58–7.52(m,2H),7.31(d,J＝3.9Hz,1H),7.10–6.99(m,2H),6.94–6.88(m,1H),6.48(s,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.79–4.70(m,2H),4.59(q,J＝17.6Hz,2H),4.47–4.35(m,1H),4.09–4.02(m,1H),4.02–3.94(m,2H),3.81–3.71(m,1H),3.36–3.32(m,2H),2.99–2.88(m,1H),2.84(s,3H),2.82–2.76(m,1H),2.52(ddd,J＝26.5,13.2,4.6Hz,1H),2.45–2.38(m,2H),2.36–2.25(m,2H),2.24–2.15(m,1H).LCMS(ESI)m/z:C 39 H 39 FN 7 O 6 S + [M+H] + Calculated 752.27; found 752.3.
Example 91: preparation of 2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide (GT-03546)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03546) (white solid, 28mg, yield 18%) was prepared using 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (4- (piperazin-1-yl) piperidin-1-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-71) and 3- (5- (bromomethyl) -1-oxo isoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 43. 1 H NMR(400MHz,MeOD)δ7.90(d,J＝7.8Hz,1H),7.80(s,1H),7.70(d,J＝7.1Hz,1H),7.57(s,1H),7.52–7.44(m,3H),7.22(d,J＝3.7Hz,1H),7.08–7.01(m,1H),6.98(dd,J＝8.8,3.2Hz,1H),6.93–6.87(m,1H),6.46(s,1H),5.18(dd,J＝13.4,5.1Hz,1H),4.72(d,J＝17.5Hz,1H),4.62–4.50(m,2H),4.37(s,2H),3.98–3.89(m,2H),3.69–3.34(m,8H),3.18–3.09(m,2H),2.98–2.87(m,1H),2.84–2.74(m,1H),2.52(qd,J＝13.3,4.7Hz,1H),2.34–2.25(m,2H),2.23–2.14(m,1H),2.08–1.93(m,2H).LCMS(ESI)C 42 H 44 FN 8 O 6 S + [M+H] + Calculated 807.31, measured 807.3.
Example 92: preparation of 2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide (GT-03503)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03503) (white solid, 27mg, yield 28%) was prepared using 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (4- (piperazin-1-yl) phenyl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-012) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 39. 1 H NMR(400MHz,MeOD)δ8.00–7.93(m,2H),7.86–7.80(m,2H),7.74(d,J＝6.8Hz,1H),7.66–7.61(m,2H),7.57(d,J＝8.2Hz,1H),7.46(d,J＝3.7Hz,1H),7.20–7.17(m,1H),7.13(d,J＝8.9Hz,2H),7.08–6.97(m,2H),6.94–6.87(m,1H),6.50(s,1H),5.20(dd,J＝13.4,5.1Hz,1H),4.65–4.51(m,4H),4.01–3.87(m,2H),3.45–3.36(m,2H),3.21–3.08(m,2H),2.99–2.87(m,1H),2.85–2.75(m,1H),2.53(qd,J＝13.4,4.9Hz,1H),2.25–2.15(m,1H).LCMS(ESI)C 43 H 39 FN 7 O 6 S + [M+H] + Calculated 800.27, measured 800.3.
Example 93: preparation of 2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide (GT-03687)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of intermediate example 40 was used to prepare 2- (5-fluoro-2-hydroxyphenyl) -2- (1-oxo-6- (6- (piperazin-1-yl) pyridazin-3-yl) isoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-D-014) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the title compound (GT-03687) (white solid, 21mg, yield 28.01%). 1 H NMR(400MHz,DMSO)δ12.63(s,1H),11.48(s,1H),11.01(s,1H),10.05(s,1H),8.36–8.27(m,3H),7.89(s,1H),7.84(d,J＝7.8Hz,1H),7.77(d,J＝7.6Hz,1H),7.71(d,J＝8.0Hz,1H),7.58(d,J＝9.5Hz,1H),7.49(d,J＝3.6Hz,1H),7.27(d,J＝3.6Hz,1H),7.15–7.09(m,1H),6.97–6.92(m,1H),6.91–6.85(m,1H),6.34(s,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.68(d,J＝17.9Hz,1H),4.53(dd,J＝19.6,5.0Hz,5H),4.37(s,1H),4.08(s,1H),3.49(dd,J＝24.7,11.4Hz,4H),3.20(ddd,J＝7.9,6.2,2.6Hz,2H),2.97–2.88(m,1H),2.64–2.58(m,1H),2.46–2.38(m,1H),2.02(dd,J＝12.0,6.2Hz,1H).LCMS(ESI)C 41 H 37 FN 9 O 6 S + [M+H] + Calculated 802.25, measured 802.30.
Example 94: preparation of 3- (5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03475)
Referring to scheme 11, step 2 and the procedure of example 1, N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (piperazin-1-yl) -1H-pyrazolo [4,3-c ] prepared in intermediate example 54 was employed]Preparation of the target Compounds of pyridin-6-amine (GT-D-18) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione(GT-03475) (white solid, 32.8mg, 40% yield). 1 H NMR(400MHz,MeOD)δ9.38(s,1H),8.99(s,1H),8.63–8.53(m,2H),7.97–7.89(m,2H),7.80(d,J＝8.1Hz,1H),7.62(s,1H),7.23(d,J＝5.8Hz,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.68–4.53(m,4H),4.34–4.26(m,1H),3.92–3.34(m,8H),3.14–3.05(m,1H),2.98–2.87(m,1H),2.84–2.76(m,1H),2.54(qd,J＝13.2,4.6Hz,1H),2.25–2.16(m,1H),1.55(d,J＝6.6Hz,6H),1.49–1.43(m,2H),1.31–1.24(m,2H).LCMS(ESI)C 37 H 41 N 12 O 5 + [M+H] + Calculated 765.30, measured 765.3.
Example 95: preparation of 3- (5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03548)
Referring to scheme 11, step 2 and the procedure of example 1, N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (4-methylamino) piperidin-1-yl) -1H-pyrazolo [4,3-c ] prepared in intermediate example 55 was used ]Pyridine-6-amine (GT-D-72) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03548) (white solid, 116mg, yield 74%). 1 H NMR(400MHz,MeOD)δ9.40(s,1H),9.01(s,1H),8.62–8.57(m,2H),7.92(d,J＝7.9Hz,1H),7.89(s,1H),7.77(d,J＝7.7Hz,1H),7.57(s,1H),7.16(d,J＝6.2Hz,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.66–4.53(m,2H),4.46–4.34(m,3H),3.79–3.69(m,1H),3.27–3.18(m,2H),3.14–3.07(m,1H),2.98–2.87(m,1H),2.83(s,3H),2.82–2.76(m,1H),2.53(qd,J＝13.2,4.6Hz,1H),2.44–2.35(m,2H),2.25–2.11(m,3H),1.56(d,J＝6.6Hz,6H),1.50–1.44(m,2H),1.32–1.25(m,2H).LCMS(ESI)C 39 H 45 N 12 O 5 S + [M+H] + Calculated 793.34, measured 793.4.
Example 96: preparation of 3- (5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03547)
Referring to scheme 11, step 2 and the procedure of example 1, N- (2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) -1-isopropyl-3- (4- (piperazin-1-yl) piperidin-1-yl) -1H-pyrazolo [4,3-c ] prepared in intermediate example 56 was used]Pyridine-6-amine (GT-D-73) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03547) (white solid, 28mg, yield 18%). 1 H NMR(400MHz,MeOD)δ9.33(s,1H),8.98(s,1H),8.66–8.56(m,2H),7.96–7.84(m,2H),7.76(s,1H),7.49(s,1H),7.13(s,1H),5.23–5.15(m,1H),4.57(d,J＝7.9Hz,1H),4.53–4.42(m,2H),4.34(d,J＝11.4Hz,2H),3.99–3.32(m,12H),3.22–3.17(m,1H),3.13–3.01(m,1H),2.97–2.86(m,1H),2.85–2.75(m,1H),2.57–2.46(m,1H),2.41–2.31(m,2H),2.24–2.14(m,1H),2.12–1.99(m,2H),1.55(d,J＝6.3Hz,4H),1.50–1.43(m,2H),1.40–1.33(m,2H),1.31–1.24(m,2H).LCMS(ESI)C 42 H 50 N 13 O 5 S + [M+H] + Calculated 848.38, measured 848.4.
Example 97: preparation of 3- (5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03506)
Referring to scheme 11, step 2 and the procedure of example 1, 1-isopropyl-N- (2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) -3- (4- (methylamino) piperidin-1-yl) -1H-pyrazolo [4,3-c ] prepared in intermediate example 57 was used]Pyridine-6-amine (GT-D-74) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03506) (white solid, 76mg, yield 45%). 1 H NMR(400MHz,MeOD)δ9.44(s,1H),8.04(d,J＝7.1Hz,1H),7.94–7.89(m,2H),7.81(s,1H),7.79–7.75(m,1H),6.59(d,J＝7.1Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.80–4.77(m,1H),4.61–4.51(m,2H),4.46–4.35(m,3H),3.96–3.85(m,2H),3.83–3.67(m,4H),3.65–3.57(m,1H),3.39(s,3H),3.27–3.19(m,2H),2.94–2.86(m,1H),2.82(s,3H),2.80–2.75(m,1H),2.59–2.46(m,1H),2.43–2.35(m,2H),2.23–2.13(m,3H),2.05–1.95(m,2H),1.82–1.73(m,2H),1.56(d,J＝6.6Hz,6H).LCMS(ESI)C 39 H 50 N 11 O 4 + [M+H] + Calculated 736.40, measured 736.4.
Example 98: preparation of 3- (5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03504)
Referring to scheme 11, step 2 and the procedure of example 1, 1-isopropyl-N- (2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) -3- (4- (piperazin-1-yl) piperidin-1-yl) -1H-pyrazolo [4,3-c ] prepared in intermediate example 58 was used]Pyridine-6-amine (GT-D-75) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03504) (white solid, 73mg, yield 47%). 1 H NMR(400MHz,MeOD)δ9.37(s,1H),8.03(d,J＝7.1Hz,1H),7.96–7.89(m,2H),7.84–7.75(m,2H),6.58(d,J＝7.1Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.66–4.52(m,4H),4.35(d,J＝13.0Hz,2H),4.14–3.53(m,16H),3.39(s,3H),3.22–3.18(m,1H),2.99–2.86(m,1H),2.83–2.74(m,1H),2.53(qd,J＝13.3,4.7Hz,1H),2.40–2.31(m,2H),2.24–2.15(m,1H),2.13–1.94(m,4H),1.83–1.68(m,2H),1.55(d,J＝6.5Hz,6H).LCMS(ESI)C 42 H 55 N 12 O 4 + [M+H] + Calculated 791.45, measured 791.4.
Example 99: preparation of 3- (5- ((4- (1- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03957)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03957) (white solid, 10mg, 14% yield) was prepared using (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-52) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared in intermediate example 81, 1 H NMR(500MHz,DMSO)δ12.92(s,1H),11.01(d,J＝11.7Hz,1H),8.85(dt,J＝90.9,31.0Hz,4H),8.33(s,1H),7.83(ddd,J＝43.8,32.1,8.1Hz,4H),7.38(s,1H),6.79(s,1H),5.17–5.11(m,1H),4.61–4.29(m,4H),3.78(d,J＝13.7Hz,3H),3.75–3.59(m,6H),3.21(t,J＝22.5Hz,6H),2.97–2.90(m,1H),2.75(s,1H),2.64–2.59(m,1H),2.42(dd,J＝13.4,8.3Hz,1H),2.19(s,2H),2.13–2.08(m,3H),2.05(t,J＝12.7Hz,7H),1.92(d,J＝8.8Hz,2H).LCMS(ESI)m/z:C 45 H 52 BrN 11 O 5 P + [M+H] + calculated 936.31; found 936.3.
Example 100: preparation of N- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide (GT-03545)
The title compound (GT-03545) (white solid, 100mg, 51% yield) was obtained by the method of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ8.23(s,1H),7.93(d,J＝7.9Hz,1H),7.86(s,1H),7.74(d,J＝7.8Hz,1H),7.37(dd,J＝7.0,2.3Hz,1H),7.29–7.20(m,2H),6.44(s,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.75(d,J＝13.7Hz,1H),4.61–4.52(m,2H),4.39(d,J＝12.9Hz,1H),3.87–3.76(m,1H),3.30–3.11(m,4H),2.99–2.87(m,1H),2.83–2.80(m,1H),2.79(s,3H),2.64(s,3H),2.52(ddd,J＝26.2,13.2,4.7Hz,1H),2.43–2.35(m,2H),2.32(s,3H),2.24–2.14(m,1H),2.08–1.92(m,2H).LCMS(ESI)C 36 H 39 ClN 9 O 4 S + [M+H] + Calculated 728.25, measured 728.3.
Example 101: preparation of N- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide (GT-03476)
The title compound (GT-03476) (white solid, 32.1mg, 39% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ8.22(s,1H),7.87(d,J＝7.8Hz,1H),7.75(s,1H),7.66(d,J＝7.9Hz,1H),7.41–7.33(m,1H),7.26(d,J＝7.2Hz,2H),6.43(s,1H),5.17(dd,J＝13.4,5.3Hz,1H),4.60–4.47(m,3H),4.23(s,2H),3.90–3.38(m,8H),3.26–3.14(m,4H),2.94–2.85(m,1H),2.84–2.75(m,1H),2.63(s,3H),2.55–2.46(m,1H),2.37–2.27(m,5H),2.22–2.15(m,1H),1.89–1.76(m,2H).LCMS(ESI)C 39 H 44 ClN 10 O 4 S + [M+H] + Calculated 783.30, measured 783.3.
Example 102: preparation of 4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-03990)
The title compound (GT-03990) (white solid, 15mg, yield 29.9%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ9.55(s,1H),9.19(d,J＝8.2Hz,1H),8.83(d,J＝5.4Hz,1H),8.49(d,J＝5.3Hz,1H),8.20(s,1H),8.05(dd,J＝8.2,5.7Hz,1H),7.97(d,J＝8.2Hz,2H),7.82(d,J＝7.8Hz,1H),7.67(s,1H),7.59(d,J＝8.1Hz,3H),7.46(d,J＝5.4Hz,1H),7.29–7.17(m,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.46(q,J＝17.4Hz,6H),2.86–2.62(m,5H),2.40(dt,J＝13.7,8.7Hz,1H),2.23(s,3H),2.13–2.02(m,1H).LCMS(ESI)C 39 H 37 N 8 O 4 + [M+H] + Calculated 681.29, measured 681.3.
Example 103: preparation of 4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-03549)
Referring to scheme 11, step 2 and the procedure of example 1, N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- (piperazin-1-yl) benzamide (CAS number 2296714-70-8) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were used to prepare the title compound (GT-03549) (white solid, 91mg, 55% yield). 1 H NMR(400MHz,MeOD)δ9.68(d,J＝1.7Hz,1H),9.35(d,J＝8.2Hz,1H),8.98(d,J＝5.7Hz,1H),8.59(d,J＝5.7Hz,1H),8.25–8.16(m,2H),7.98–7.90(m,3H),7.88(s,1H),7.76(d,J＝7.9Hz,1H),7.65(d,J＝5.7Hz,1H),7.39–7.29(m,2H),7.11(d,J＝9.0Hz,2H),5.19(dd,J＝13.3,5.2Hz,1H),4.65–4.53(m,2H),4.14–3.99(m,2H),3.68–3.53(m,2H),3.39–3.31(m,4H),3.29–3.14(m,2H),2.98–2.87(m,1H),2.84–2.75(m,1H),2.53(qd,J＝13.3,4.9Hz,1H),2.33(s,3H),2.24–2.15(m,1H).LCMS(ESI)C 41 H 40 N 9 O 4 + [M+H] + Calculated 722.32, measured 722.3.
Example 104: preparation of 4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-03640)
The title compound (GT-03640) (white solid, 16mg, yield 18%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ9.72(s,1H),9.41(d,J＝8.3Hz,1H),9.05(d,J＝5.5Hz,1H),8.60(d,J＝6.0Hz,1H),8.27(dd,J＝8.2,5.9Hz,1H),8.19(s,1H),7.99(d,J＝8.8Hz,2H),7.92(d,J＝7.8Hz,1H),7.87(s,1H),7.78–7.74(m,2H),7.44(d,J＝8.3Hz,1H),7.40–7.29(m,3H),5.18(dd,J＝13.4,5.1Hz,1H),4.76–4.71(m,1H),4.63–4.55(m,2H),4.42(d,J＝11.7Hz,1H),4.13–4.03(m,2H),3.80–3.71(m,1H),3.27–3.19(m,2H),2.96–2.87(m,1H),2.82(s,3H),2.79–2.73(m,1H),2.57–2.49(m,1H),2.43–2.37(m,2H),2.36(s,3H),2.25–2.16(m,3H).LCMS(ESI)m/z:C 43 H 44 N 9 O 4 + [M+H] + Calculated 750.35; found 750.4.
Example 105: preparation of 4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-03689)
The title compound (GT-03689) (white solid, 21mg, yield 28.06%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.00(s,1H),9.96(s,1H),9.44(s,1H),9.14(s,1H),8.94(d,J＝8.2Hz,1H),8.89(d,J＝5.0Hz,1H),8.59(d,J＝5.1Hz,1H),8.11(s,1H),7.94–7.87(m,4H),7.81(s,2H),7.55(d,J＝5.2Hz,1H),7.46(dd,J＝8.3,1.9Hz,1H),7.19(d,J＝8.6Hz,1H),7.05(d,J＝8.9Hz,2H),5.16–5.11(m,1H),4.48(s,2H),4.39(s,1H),4.07(d,J＝11.6Hz,3H),3.75–3.66(m,3H),3.49(ddd,J＝17.8,12.4,7.8Hz,3H),2.99–2.78(m,4H),2.60(dd,J＝16.1,1.8Hz,1H),2.48–2.37(m,2H),2.25–2.12(m,6H),2.01(dd,J＝9.0,3.4Hz,1H),1.82–1.72(m,2H).LCMS(ESI)C 46 H 49 N 10 O 4 + [M+H] + Calculated 805.39, measured 805.40.
Example 106: preparation of 4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile (GT-03528)
Referring to the procedure of scheme 12, the title compound (GT-03528) was prepared using 4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7-hydroxy-6-methoxyquinoline-3-carbonitrile (CAS number: 1460227-29-5) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (white solid, 53mg, 30% yield). 1 H NMR(400MHz,MeOD)δ8.83(s,1H),8.00(s,1H),7.88(d,J＝7.9Hz,1H),7.77(s,1H),7.70(d,J＝7.2Hz,1H),7.67(s,1H),7.40(d,J＝8.3Hz,2H),5.55(s,2H),5.18(dd,J＝13.3,5.2Hz,1H),4.54(q,J＝17.2Hz,2H),4.10(s,3H),3.93(s,3H),2.98–2.86(m,1H),2.84–2.74(m,1H),2.57–2.43(m,1H),2.24–2.14(m,1H).LCMS(ESI)C 32 H 26 Cl 2 N 5 O 6 + [M+H] + Calculated 646.13, measured 646.2.
Example 107: preparation of N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03804)
Referring to scheme 11, step 2 and the procedure of example 1, 3- (imidazo [1,2-b ] prepared in intermediate example 68 is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide hydrochloride (GT-D-109) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-03804) (white solid, 26mg, yield 31%), 1 H NMR(400MHz,MeOD)δ8.95(dd,J＝4.5,1.4Hz,1H),8.44(s,1H),8.38(dd,J＝9.3,1.4Hz,1H),8.25–8.17(m,2H),8.05(d,J＝7.8Hz,1H),7.96(dd,J＝8.0,1.9Hz,1H),7.91(d,J＝7.8Hz,1H),7.83–7.75(m,3H),7.70(d,J＝7.7Hz,1H),7.53(d,J＝8.1Hz,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.56(q,J＝17.5Hz,2H),4.45(s,2H),3.95(s,2H),3.75–3.32(m,8H),2.93–2.87(m,1H),2.83–2.76(m,1H),2.68(s,3H),2.58–2.45(m,1H),2.23–2.15(m,1H).LCMS(ESI)m/z:C 42 H 38 F 3 N 8 O 4 + [M+H] + calculated 775.30; found 775.3.
Example 108: preparation of N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03933)
Referring to scheme 11 and the procedure of example 1, 3- (imidazo [1, 2-b) prepared in intermediate example 68 is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide hydrochloride (GT-D-109) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03933) (white solid, 53mg, yield 65%). 1 H NMR(400MHz,DMSO)δ11.03(s,1H),10.71(s,1H),8.75(dd,J＝4.4,1.3Hz,1H),8.33–8.26(m,3H),8.23(d,J＝1.5Hz,1H),8.20–8.13(m,1H),8.01–7.94(m,1H),7.86(s,1H),7.74–7.67(m,1H),7.64–7.60(m,1H),7.57(d,J＝8.2Hz,1H),7.43(dd,J＝9.2,4.5Hz,1H),5.19–5.09(m,2H),4.92(s,1H),4.65–4.49(m,4H),3.48–3.06(m,6H),2.97–2.86(m,2H),2.69–2.64(m,1H),2.61(s,3H),2.60–2.57(m,1H),2.46–2.40(m,1H),2.04–1.97(m,1H).LCMS(ESI)m/z:C 42 H 37 F 4 N 8 O 4 + [M+H] + Calculated 793.29; found 793.3.
Example 109: preparation of N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03934)
The title compound (GT-03934) (white solid, 44mg, 54% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.70(s,1H),8.75(dd,J＝4.4,1.4Hz,1H),8.33–8.26(m,3H),8.23(d,J＝1.7Hz,1H),8.17(d,J＝7.9Hz,1H),8.01–7.91(m,3H),7.66(d,J＝8.4Hz,1H),7.57(d,J＝8.4Hz,1H),7.43(dd,J＝9.2,4.5Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.90(s,1H),4.58–4.43(m,5H),3.43–3.11(m,6H),2.97–2.86(m,2H),2.71–2.64(m,1H),2.62(s,3H),2.59–2.55(m,1H),2.45–2.37(m,1H),2.06–1.97(m,1H).LCMS(ESI)m/z:C 42 H 37 F 4 N 8 O 4 + [M+H] + Calculated 793.29; found 793.3.
Example 110: preparation of N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03935)
Referring to scheme 11 and the procedure of example 1, 3- (imidazo [1, 2-b) prepared in intermediate example 68 is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide hydrochloride (GT-D-109) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-03935) (white solid, 62mg, yield 76%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.68(s,1H),8.75(d,J＝4.2Hz,1H),8.33–8.26(m,3H),8.23(s,1H),8.16(d,J＝7.8Hz,1H),7.97(d,J＝8.0Hz,1H),7.70–7.51(m,4H),7.46–7.37(m,2H),3.39–3.02(m,6H),2.97–2.87(m,2H),2.65–2.60(m,4H),2.60–2.57(m,1H),2.41–2.34(m,1H),2.04–1.98(m,1H).LCMS(ESI)m/z:C 42 H 37 F 4 N 8 O 4 + [M+H] + Calculated 793.29; found 793.3.
Example 111: preparation of N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03939)
The title compound (GT-03939) (white solid, 40mg, 50% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.05(s,1H),10.68(s,1H),8.77–8.73(m,1H),8.31–8.26(m,3H),8.23(d,J＝1.7Hz,1H),8.17(d,J＝8.3Hz,1H),7.97(d,J＝8.0Hz,1H),7.92(s,1H),7.81(d,J＝6.9Hz,1H),7.75–7.68(m,1H),7.62(t,J＝7.6Hz,1H),7.57(d,J＝8.2Hz,1H),7.45–7.39(m,1H),5.18(dd,J＝13.2,5.1Hz,1H),4.86–4.71(m,1H),4.58–4.45(m,3H),3.51–3.01(m,6H),3.01–2.90(m,2H),2.68–2.66(m,1H),2.62(s,3H),2.58–2.53(m,1H),2.39–2.31(m,1H),2.10–2.01(m,1H).LCMS(ESI)m/z:C 42 H 38 F 3 N 8 O 4 + [M+H] + Calculated 775.30; found 775.3.
Example 112: preparation of N- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03805)
Referring to scheme 11, step 2 and the procedure of example 1, 3- (imidazo [1,2-b ] prepared in example 69 is used as an intermediate]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-110) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-03805) (white solid, 48mg, yield 60%), 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.86(s,1H),10.60(s,1H),8.73(dd,J＝4.4,1.5Hz,1H),8.27(dd,J＝9.2,1.5Hz,1H),8.25(s,1H),8.23–8.20(m,2H),8.16–8.10(m,1H),7.96(dd,J＝8.0,1.8Hz,1H),7.90(s,1H),7.85(d,J＝7.8Hz,1H),7.80(d,J＝7.8Hz,1H),7.56(dd,J＝8.6,3.0Hz,2H),7.41(dd,J＝9.2,4.5Hz,1H),5.15(dd,J＝13.3,5.0Hz,1H),4.62–4.56(m,2H),4.46(dd,J＝52.1,17.7Hz,2H),3.44–3.40(m,2H),3.30–3.16(m,4H),3.11–3.01(m,2H),3.00–2.87(m,1H),2.68–2.63(m,1H),2.61(s,3H),2.46–2.37(m,1H),2.06–1.98(m,1H).LCMS(ESI)m/z:C 41 H 36 F 3 N 8 O 4 + [M+H] + calculated 761.28; found 761.3.
Example 113: preparation of 7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (GT-03544)
Referring to scheme 11, step 2 and the procedure of example 1, 7-cyclopentyl-N, N-dimethyl-2- ((5- (4- (methylamino) piperidin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d ] prepared using intermediate example 59]Pyrimidine-6-carboxamide (GT-D-79) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03544) (white solid, 100mg, 60% yield). 1 H NMR(400MHz,MeOD)δ8.98(s,1H),8.10(dd,J＝9.6,2.9Hz,1H),7.96–7.90(m,2H),7.87(s,1H),7.75(d,J＝7.9Hz,1H),7.45(d,J＝9.5Hz,1H),6.81(s,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.80–4.75(m,2H),4.65–4.53(m,2H),4.41(d,J＝13.1Hz,1H),4.00–3.90(m,2H),3.68–3.59(m,1H),3.16(d,J＝7.7Hz,6H),3.00–2.87(m,3H),2.82(s,3H),2.81–2.73(m,1H),2.60–2.42(m,3H),2.40–2.31(m,2H),2.25–2.17(m,1H),2.16–2.02(m,6H),1.81–1.68(m,2H).LCMS(ESI)C 39 H 47 N 10 O 4 + [M+H] + Calculated 719.38, measured 719.4.
Example 114: preparation of 7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (GT-03550)
Referring to scheme 11, step 2 and the procedure of example 1, 7-cyclopentyl-N, N-dimethyl-2- ((5- (4-piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d ] prepared by intermediate example 60]Pyrimidine-6-carboxamide (GT-D-80) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03550) (white solid, 107mg, 67% yield). 1 H NMR(400MHz,MeOD)δ8.98(s,1H),8.09(d,J＝7.8Hz,1H),8.02–7.88(m,3H),7.81(d,J＝7.7Hz,1H),7.44(d,J＝9.5Hz,1H),6.81(s,1H),5.18(dd,J＝13.7,4.9Hz,1H),4.82–4.78(m,1H),4.70–4.65(m,1H),4.65–4.52(m,2H),4.01–3.60(m,9H),3.16(d,J＝6.3Hz,6H),3.04–2.74(m,4H),2.65–2.31(m,5H),2.24–1.95(m,6H),1.81–1.63(m,2H),1.42–1.33(m,2H).LCMS(ESI)C 42 H 52 N 11 O 4 + [M+H] + Calculated value 744.42, measured value 744.4.
Example 115: preparation of 3- (5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03688)
Referring to scheme 11, step 2 and the method of example 1, 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] is used]Imidazol-6-yl) -N- (5- (piperazin-1-yl) pyridin-2-yl) pyrimidin-2-amine (CAS no: 1873303-25-3) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione the title compound (GT-03688) was prepared (white solid, 18mg, yield 22.74%). 1 H NMR(400MHz,DMSO)δ12.00(s,1H),11.54(s,1H),11.02(s,1H),9.42(s,1H),8.83(d,J＝3.4Hz,1H),8.30(s,1H),8.06(d,J＝9.4Hz,1H),7.97(s,2H),7.88(d,J＝9.5Hz,1H),7.83(s,2H),7.78(d,J＝11.7Hz,1H),5.15(dd,J＝13.2,5.1Hz,1H),4.89(dd,J＝13.9,7.0Hz,1H),4.52(d,J＝17.5Hz,3H),4.36(s,1H),3.81(s,1H),3.44(d,J＝6.7Hz,2H),3.34(t,J＝12.6Hz,2H),3.23(dd,J＝18.6,10.7Hz,2H),2.98–2.89(m,1H),2.73(s,3H),2.61(dd,J＝15.9,1.4Hz,1H),2.44(dd,J＝13.1,4.5Hz,1H),2.05–1.98(m,1H),1.64(d,J＝6.9Hz,6H).LCMS(ESI)C 38 H 39 F 2 N 10 O 3 + [M+H] + Calculated 721.31, measured 721.30.
Example 116: preparation of 3- (5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03639)
Referring to scheme 11, step 2 and the method of example 1, 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] is used]Imidazol-6-yl) -N- (5- (4- (methylamino) piperidin-1-yl) pyridin-2-yl) pyrimidin-2-amine (CAS no: 2756101-77-4) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03639) (white solid, 24mg, yield 29%). 1 H NMR(400MHz,MeOD)δ8.83(d,J＝3.4Hz,1H),8.52(s,1H),8.27(dd,J＝9.7,2.8Hz,1H),8.10(d,J＝11.1Hz,1H),7.94(d,J＝7.9Hz,1H),7.90–7.85(m,2H),7.75(d,J＝8.2Hz,1H),7.55(d,J＝9.7Hz,1H),5.19(dd,J＝13.2,5.1Hz,1H),5.09(dt,J＝14.0,7.0Hz,1H),4.78(d,J＝12.6Hz,1H),4.59(q,J＝17.6Hz,2H),4.42(d,J＝12.6Hz,1H),4.05–3.94(m,2H),3.71–3.61(m,1H),3.05–2.92(m,3H),2.90(s,3H),2.82(s,3H),2.81–2.75(m,1H),2.53(qd,J＝13.2,4.7Hz,1H),2.42–2.34(m,2H),2.25–2.07(m,3H),1.79(d,J＝6.9Hz,6H).LCMS(ESI)m/z:C 40 H 43 F 2 N 10 O 3 + [M+H] + ,749.35；found,749.3.
Example 117: preparation of 3- (5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03719)
Referring to scheme 11, step 2 and the method of example 1, 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] is used]Imidazol-6-yl) -N- (5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1873300-67-4) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione the title compound (GT-03719) was prepared (white solid, 22mg, yield 31.33%). 1 H NMR(400MHz,DMSO)δ11.62(s,1H),11.01(s,1H),8.84(d,J＝3.4Hz,1H),8.27(s,1H),8.16(d,J＝9.5Hz,1H),7.93(dd,J＝8.5,3.5Hz,2H),7.77(dd,J＝13.3,11.8Hz,4H),5.14(dd,J＝13.0,5.3Hz,1H),4.90(dd,J＝13.8,6.8Hz,1H),4.45(td,J＝33.7,16.7Hz,6H),3.87(d,J＝11.1Hz,3H),3.74–3.65(m,3H),3.49–3.41(m,2H),2.96–2.89(m,1H),2.81(t,J＝12.0Hz,2H),2.71(s,3H),2.61(d,J＝17.2Hz,1H),2.47–2.35(m,2H),2.25–2.15(m,2H),2.04–1.99(m,1H),1.90–1.79(m,2H),1.63(d,J＝6.9Hz,6H).LCMS(ESI)C 43 H 48 F 2 N 11 O 3 + [M+H] + Calculated 804.38, measured 804.40.
Example 118: preparation of 3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03601)
Preparation of the target Compound (GT-03601) (white solid) by the method of step 2 of scheme 11 and example 140mg, yield 49%). 1 H NMR(400MHz,MeOD)δ8.29(s,1H),8.13(s,1H),7.94(d,J＝6.1Hz,1H),7.75–7.68(m,2H),7.62(t,J＝7.5Hz,1H),7.52–7.40(m,2H),7.09(s,1H),6.89(d,J＝8.7Hz,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.66–4.57(m,2H),4.57–4.34(m,2H),4.04–3.95(m,2H),3.92(s,3H),3.88–3.77(m,1H),3.39–3.32(m,2H),3.03–2.94(m,1H),2.92(s,3H),2.84–2.76(m,1H),2.59–2.28(m,5H),2.24–2.16(m,1H),1.90(s,3H),1.87(s,3H).LCMS(ESI)C 39 H 44 ClFN 8 O 5 P + [M+H] + Calculated 789.28, measured 789.3.
Example 119: preparation of 3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03775)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03775) (white solid, 39mg, yield 63.07%) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (GT-D-39) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 23. 1 H NMR(400MHz,DMSO)δ11.96(d,J＝41.2Hz,2H),11.01(s,1H),9.48(s,1H),8.31(d,J＝27.9Hz,2H),7.98(s,1H),7.88–7.79(m,2H),7.63(dd,J＝13.8,7.5Hz,1H),7.36(d,J＝8.6Hz,2H),7.24(t,J＝7.3Hz,1H),6.73(d,J＝2.1Hz,1H),6.56(dd,J＝8.7,2.1Hz,1H),5.15(dd,J＝13.2,5.1Hz,1H),4.52(d,J＝17.2Hz,3H),4.39(d,J＝17.7Hz,1H),3.87(d,J＝11.9Hz,2H),3.78(s,3H),3.41(d,J＝10.6Hz,2H),3.34–3.27(m,2H),3.25–3.17(m,2H),2.98–2.89(m,1H),2.61(d,J＝17.0Hz,1H),2.46–2.35(m,1H),2.07–1.98(m,1H),1.81(s,3H),1.78(s,3H).LCMS(ESI)C 37 H 41 ClN 8 O 5 P + [M+H] + Calculated 743.25, measured 743.30.
Example 120: preparation of 3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03776)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03776) (white solid, 34mg, yield 53.69%) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (GT-D-39) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) prepared as intermediate example 23. 1 H NMR(400MHz,DMSO)δ11.93(s,1H),11.74(s,1H),11.03(s,1H),9.33(s,1H),8.31(d,J＝41.8Hz,2H),8.07–8.00(m,1H),7.71(d,J＝7.7Hz,1H),7.62(dd,J＝13.7,7.5Hz,1H),7.37(d,J＝8.6Hz,2H),7.22(t,J＝7.3Hz,1H),6.74(d,J＝2.0Hz,1H),6.56(dd,J＝8.7,2.0Hz,1H),5.16(dd,J＝13.2,5.1Hz,1H),4.64–4.55(m,3H),4.47(d,J＝17.6Hz,1H),3.91–3.85(m,2H),3.78(s,3H),3.58–3.50(m,2H),3.25(d,J＝20.0Hz,4H),2.98–2.89(m,1H),2.62(d,J＝17.1Hz,1H),2.44(dd,J＝13.5,4.4Hz,1H),2.03(ddd,J＝9.9,4.9,3.0Hz,1H),1.81(s,3H),1.77(s,3H).LCMS(ESI)C 37 H 40 ClFN 8 O 5 P + [M+H] + Calculated 761.25, measured 761.30.
Example 121: preparation of 3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphono) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03777)
The title compound (GT-03777) (white solid, 35mg, yield 55.27%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.93(s,2H),11.03(s,1H),9.35(s,1H),8.35(s,1H),8.26(s,1H),8.16(d,J＝6.1Hz,1H),7.69(d,J＝8.5Hz,1H),7.62(dd,J＝13.3,7.7Hz,1H),7.38(d,J＝8.6Hz,2H),7.22(t,J＝7.2Hz,1H),6.74(d,J＝1.9Hz,1H),6.55(dd,J＝8.7,2.0Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.59–4.48(m,3H),4.38(d,J＝17.5Hz,1H),3.87(s,2H),3.78(s,3H),3.50(s,2H),3.29(s,4H),2.98–2.88(m,1H),2.61(d,J＝16.9Hz,1H),2.47–2.37(m,1H),2.04(dd,J＝13.8,8.4Hz,1H),1.81(s,3H),1.77(s,3H).LCMS(ESI)C 37 H 40 ClFN 8 O 5 P + [M+H] + Calculated 761.25, measured 761.30.
Example 122: preparation of 3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphono) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03778)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03778) (white solid, 42mg, yield 66.32%) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (GT-D-39) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 23. 1 H NMR(400MHz,DMSO)δ11.99(s,2H),11.02(s,1H),9.45(s,1H),8.35(s,1H),8.27(s,1H),7.76(d,J＝8.1Hz,2H),7.62(dd,J＝13.3,7.7Hz,1H),7.37(d,J＝8.6Hz,2H),7.24(t,J＝7.3Hz,1H),6.74(d,J＝2.0Hz,1H),6.56(dd,J＝8.7,2.1Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.57–4.50(m,3H),4.41(d,J＝18.1Hz,1H),3.87(d,J＝8.7Hz,2H),3.79(s,3H),3.43(d,J＝10.1Hz,2H),3.35–3.27(m,2H),3.25–3.17(m,2H),2.97–2.88(m,1H),2.61(d,J＝16.4Hz,1H),2.45–2.37(m,1H),2.05–1.96(m,1H),1.81(s,3H),1.78(s,3H).LCMS(ESI)C 37 H 40 ClFN 8 O 5 P + [M+H] + Calculated 761.25, measured 761.30.
Example 123: preparation of 3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03779)
The title compound (GT-03779) (white solid, 28mg, yield 45.28%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.98(s,1H),11.81(s,1H),11.07(s,1H),9.43(s,1H),8.35(s,1H),8.27(s,1H),8.10(d,J＝7.4Hz,1H),7.85(d,J＝7.6Hz,1H),7.68–7.58(m,2H),7.37(d,J＝8.8Hz,2H),7.23(t,J＝7.1Hz,1H),6.74(s,1H),6.56(d,J＝8.8Hz,1H),5.20(dd,J＝12.9,4.8Hz,1H),5.00(d,J＝17.5Hz,1H),4.53(dd,J＝25.2,14.8Hz,3H),3.89(d,J＝7.3Hz,2H),3.79(s,3H),3.50(d,J＝7.9Hz,1H),3.36(dd,J＝21.2,9.4Hz,5H),2.95(dd,J＝21.8,8.8Hz,1H),2.65(d,J＝17.0Hz,1H),2.35(dt,J＝13.2,9.6Hz,1H),2.09–2.01(m,1H),1.81(s,3H),1.77(s,3H).LCMS(ESI)C 37 H 41 ClN 8 O 5 P + [M+H] + Calculated 743.25, measured 743.30.
Example 124: preparation of 3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03529)
Referring to scheme 11, step 2 and the procedure of example 1, 5-chloro-N prepared in intermediate example 20 was used 2 - (2-isopropoxy-5-methyl-4- (piperazin-1-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-86) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03529) (white solid, 77mg, yield 49%). 1 H NMR(400MHz,MeOD)δ8.35(d,J＝8.0Hz,1H),8.19(s,1H),8.00–7.92(m,2H),7.88(s,1H),7.78(d,J＝7.8Hz,1H),7.70(t,J＝7.7Hz,1H),7.56(s,1H),7.46(t,J＝7.7Hz,1H),6.80(s,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.65–4.53(m,5H),3.62–3.53(m,2H),3.45–3.34(m,3H),3.29–3.22(m,2H),3.19–3.10(m,2H),2.98–2.87(m,1H),2.84–2.76(m,1H),2.59–2.46(m,1H),2.24–2.18(m,1H),2.16(s,3H),1.30(d,J＝6.0Hz,6H),1.25(d,J＝6.8Hz,6H).LCMS(ESI)C 41 H 48 ClN 8 O 6 S + [M+H] + Calculated 815.31, measured 815.3.
Example 125: preparation of 3- (5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03530)
Referring to scheme 11, step 2 and the procedure of example 1, 5-chloro-N prepared in intermediate example 21 was used 2 - (2-isopropoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-87) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03530) (white solid, 92mg, yield 61%). 1 H NMR(400MHz,MeOD)δ8.33–8.19(m,2H),8.03(dd,J＝7.9,1.4Hz,1H),7.94(d,J＝7.8Hz,1H),7.89(s,1H),7.82–7.71(m,2H),7.62–7.53(m,1H),7.32(s,1H),6.93(s,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.79(d,J＝13.3Hz,1H),4.75–4.65(m,2H),4.63–4.54(m,2H),4.44(d,J＝13.1Hz,1H),3.69–3.59(m,1H),3.46–3.33(m,4H),2.95–2.88(m,1H),2.85(s,3H),2.83–2.77(m,1H),2.53(qd,J＝13.2,4.6Hz,1H),2.40–2.33(m,2H),2.29–2.15(m,6H),1.29(d,J＝6.0Hz,6H),1.26(d,J＝6.8Hz,6H).LCMS(ESI)C 43 H 52 ClN 8 O 6 S + [M+H] + Calculated 843.34, measured 843.3.
Example 126: preparation of 3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03531)
Referring to scheme 11, step 2 and the procedure of example 1, 5-chloro-N prepared in intermediate example 22 was used 2 - (2-isopropoxy-5-methyl-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (GT-D-88) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03531) (white solid, 58mg, 39% yield). 1 H NMR(400MHz,MeOD)δ8.36–8.14(m,2H),8.02(d,J＝7.9Hz,1H),7.87(d,J＝7.8Hz,1H),7.82–7.72(m,2H),7.69(d,J＝7.8Hz,1H),7.56(t,J＝7.6Hz,1H),7.37–7.22(m,1H),6.83(s,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.69–4.61(m,1H),4.55(q,J＝17.4Hz,2H),4.24(s,2H),3.93–3.36(m,8H),3.13–2.70(m,5H),2.59–2.44(m,1H),2.34–2.25(m,2H),2.24–2.14(m,4H),2.08–1.94(m,2H),1.28(d,J＝6.0Hz,6H),1.25(d,J＝6.8Hz,6H).LCMS(ESI)C 46 H 57 ClN 9 O 6 S + [M+H] + Calculated 898.38, measured 898.4.
Example 127: preparation of 8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03758)
Reference toScheme 11 and example 1, using intermediate example 45 prepared 9-ethyl-6, 6-dimethyl-11-oxo-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ]]Carbazole-3-carbonitrile (GT-D-113) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03758) (white solid, 22mg, yield 26%). 1 H NMR(400MHz,DMSO)δ12.85(s,1H),11.02(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.00(s,1H),7.77(s,1H),7.66(d,J＝7.6Hz,1H),7.60(dd,J＝8.2,1.2Hz,1H),7.36(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.60(d,J＝17.5Hz,1H),4.43(d,J＝17.5Hz,1H),4.15(s,2H),3.47–3.22(m,10H),3.00–2.87(m,2H),2.86–2.76(m,2H),2.74–2.68(m,2H),2.64–2.58(m,1H),2.47–2.41(m,1H),2.27–2.18(m,2H),2.07–1.99(m,1H),1.96–1.86(m,2H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).LCMS(ESI)m/z:C 44 H 47 FN 7 O 4 + [M+H] + Calculated 756.37; measured value 756.4
Example 128: preparation of 8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03759)
The title compound (GT-03759) (white solid, 32mg, 38% yield) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ12.83(s,1H),11.01(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.00(s,1H),7.84(s,1H),7.65–7.56(m,2H),7.36(s,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.48(d,J＝17.5Hz,1H),4.36(d,J＝17.1Hz,1H),4.08(s,2H),3.46–3.18(m,10H),2.98–2.87(m,2H),2.82(t,J＝11.5Hz,2H),2.71(q,J＝7.4Hz,2H),2.64–2.59(m,1H),2.46–2.39(m,1H),2.25–2.17(m,2H),2.07–2.00(m,1H),1.95–1.86(m,2H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).LCMS(ESI)m/z:C 44 H 47 FN 7 O 4 + [M+H] + Calculated 756.37; found 756.4.
Example 129: preparation of 8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03760)
Referring to scheme 11 and the method of example 1, 9-ethyl-6, 6-dimethyl-11-oxo-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] prepared in intermediate example 45 was used ]Carbazole-3-carbonitrile (GT-D-113) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-03760) (white solid, 40mg, yield 47%). 1 H NMR(400MHz,DMSO)δ12.83(s,1H),11.02(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.00(s,1H),7.67–7.47(m,3H),7.36(s,1H),5.10(dd,J＝13.3,5.0Hz,1H),4.51(d,J＝18.2Hz,1H),4.38(d,J＝17.9Hz,1H),4.20(s,2H),3.50–3.23(m,10H),2.97–2.87(m,2H),2.86–2.78(m,2H),2.71(q,J＝7.5Hz,2H),2.65–2.58(m,1H),2.46–2.35(m,1H),2.27–2.18(m,2H),2.05–1.98(m,1H),1.95–1.86(m,2H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).LCMS(ESI)m/z:C 44 H 47 FN 7 O 4 + [M+H] + Calculated 756.37; found 756.4.
Example 130: preparation of 8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03764)
The title compound (GT-03764) (white solid, 44mg, yield 54%) was prepared according to the procedure of step 2 of scheme 11 and example 1, 1 H NMR(400MHz,DMSO)δ12.83(s,1H),11.05(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.00(s,1H),7.85–7.71(m,2H),7.60(dd,J＝8.2,1.3Hz,2H),7.36(s,1H),5.17(dd,J＝12.9,5.2Hz,1H),4.70–4.41(m,2H),3.54–3.14(m,11H),3.00–2.94(m,1H),2.82(t,J＝11.5Hz,2H),2.71(q,J＝7.6Hz,2H),2.67–2.61(m,1H),2.45–2.31(m,1H),2.28–2.18(m,2H),2.09–2.01(m,1H),1.98–1.87(m,2H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).LCMS(ESI)m/z:C 44 H 48 N 7 O 4 + [M+H] + calculated 738.38; measured value 738.4
Example 131: preparation of 8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03474)
Referring to scheme 11, step 2 and the procedure of example 1, 9-ethyl-6, 6-dimethyl-8- (4- (methylamino) piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] prepared in intermediate example 46 was used]Carbazole-3-carbonitrile (GT-D-85) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03474) (white solid, 23.5mg, yield 29%). 1 H NMR(400MHz,MeOD)δ8.41(d,J＝8.1Hz,1H),8.20(s,1H),7.96(d,J＝7.8Hz,1H),7.86(d,J＝9.8Hz,2H),7.76(d,J＝7.9Hz,1H),7.55(dd,J＝8.2,1.2Hz,1H),7.41(s,1H),5.20(dd,J＝13.3,5.1Hz,1H),4.60(q,J＝17.6Hz,2H),4.10(q,J＝7.1Hz,2H),3.49–3.36(m,2H),2.99–2.92(m,2H),2.88–2.80(m,5H),2.53(qd,J＝13.2,4.6Hz,1H),2.38–2.30(m,2H),2.25–2.09(m,3H),2.01(s,3H),1.81(s,6H),1.24(t,J＝7.1Hz,3H).LCMS(ESI)C 41 H 43 ClN 6 O 4 + [M+H] + Calculated 683.33, measured 683.3.
Example 132: preparation of 3- (5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03707)
Referring to scheme 11, step 2 and the procedure of example 1, the 5, 7-dimethoxy-2- (4- (4- (methylamino) piperidin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-93) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 62 was used to afford the title compound (GT-03707) (white solid, 32mg, yield 38.02%). 1 HNMR(400MHz,DMSO)δ10.98(s,1H),8.08(d,J＝8.9Hz,2H),7.95(s,1H),7.67(d,J＝7.8Hz,1H),7.55(s,1H),7.46(d,J＝7.9Hz,1H),7.01(d,J＝9.0Hz,2H),6.68(d,J＝2.1Hz,1H),6.46(d,J＝2.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.3Hz,1H),4.31(d,J＝17.3Hz,1H),3.99(d,J＝12.3Hz,2H),3.88(s,3H),3.83(s,3H),3.69(s,2H),2.93(dd,J＝13.9,5.4Hz,1H),2.83(t,J＝12.5Hz,2H),2.68–2.57(m,2H),2.40(dd,J＝13.0,8.8Hz,1H),2.13(s,3H),2.03–1.98(m,1H),1.88(d,J＝10.7Hz,2H),1.59(dd,J＝20.8,10.7Hz,2H).LCMS(ESI)C 36 H 39 N 6 O 6 + [M+H] + Calculated 651.29, measured 651.30.
Example 133: preparation of 3- (5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione (GT-03708)
Referring to scheme 11, step 2 and the procedure of example 1, the 5, 7-dimethoxy-2- (4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) quinazolin-4 (3H) -one (GT-D-94) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 63 was used to give the title compound (GT-03708) (white solid, 29mg, yield 36.20%). 1 HNMR(400MHz,DMSO)δ11.72(s,1H),10.98(s,1H),8.07(d,J＝8.9Hz,2H),7.95(s,1H),7.67(d,J＝7.7Hz,1H),7.53(s,1H),7.43(d,J＝7.8Hz,1H),6.99(d,J＝9.0Hz,2H),6.67(d,J＝2.1Hz,1H),6.46(d,J＝2.0Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝17.5Hz,1H),4.31(d,J＝17.3Hz,1H),3.92(d,J＝12.9Hz,2H),3.88(s,3H),3.83(s,3H),3.56(s,2H),2.93(dd,J＝13.7,4.9Hz,1H),2.81(t,J＝11.7Hz,2H),2.70(d,J＝24.0Hz,3H),2.64–2.54(m,2H),2.46–2.34(m,6H),1.99(ddd,J＝13.2,5.7,3.1Hz,1H),1.83(d,J＝11.5Hz,2H),1.44(tt,J＝12.8,6.6Hz,2H).LCMS(ESI)C 39 H 44 N 7 O 6 + [M+H] + Calculated 706.33, measured 706.40.
Example 134: preparation of N- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (GT-03690)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03690) (white solid, 16mg, yield 21.06%) was prepared using N- (tert-butyl) -3- ((5-methyl-2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-D-89) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 18. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.98(s,1H),7.99–7.92(m,3H),7.89–7.80(m,3H),7.72(d,J＝7.9Hz,1H),7.60(dd,J＝17.1,9.1Hz,3H),7.29(d,J＝8.1Hz,2H),7.19–6.96(m,2H),5.14(dd,J＝13.2,5.0Hz,1H),4.64–4.58(m,1H),4.50(t,J＝6.7Hz,1H),4.41–4.34(m,2H),3.45(ddd,J＝18.1,10.6,6.3Hz,2H),2.96–2.79(m,3H),2.70–2.56(m,5H),2.44–2.27(m,3H),2.18(s,3H),2.02(dd,J＝10.8,5.7Hz,3H),1.09(s,9H).LCMS(ESI)C 41 H 50 N 9 O 5 S + [M+H] + Calculated 780.36, measured 780.40.
Example 135: preparation of N- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide (GT-03709)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03709) (white solid, 23mg, yield 36.54%) was prepared using N- (tert-butyl) -3- ((5-methyl-2- ((4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) benzenesulfonamide (GT-D-90) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 19. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.48(s,1H),9.96(s,1H),9.40(s,1H),7.96–7.86(m,4H),7.80(s,2H),7.72(d,J＝7.9Hz,1H),7.60(dd,J＝18.9,10.9Hz,2H),7.26(d,J＝8.2Hz,2H),7.02(s,2H),5.14(dd,J＝13.1,5.2Hz,1H),4.62–4.33(m,5H),3.78(d,J＝10.5Hz,5H),3.51–3.35(m,4H),3.03–2.86(m,2H),2.84–2.69(m,2H),2.63(t,J＝16.4Hz,2H),2.48–2.34(m,2H),2.18(s,3H),2.02(dd,J＝9.8,4.7Hz,1H),1.93–1.80(m,2H),1.09(s,9H).LCMS(ESI)C 44 H 55 N 10 O 5 S + [M+H] + Calculated 835.40, measured 835.40.
Example 136: preparation of 2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03595)
Referring to scheme 11 and the procedure of example 1, 2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) prepared in intermediate example 27 was used) Pyridin-4-yl) amino) -N-methylbenzamide (GT-M-12) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03595) (white solid, 37mg, yield 59%). 1 H NMR(400MHz,MeOD)δ8.03(s,1H),7.89–7.81(m,1H),7.78–7.70(m,2H),7.66–7.55(m,2H),7.42–7.33(m,1H),7.31–7.22(m,1H),7.08(s,1H),6.94(d,J＝8.8Hz,1H),6.48(s,1H),5.18(dd,J＝13.4,5.1Hz,1H),4.70–4.61(m,2H),4.53(s,2H),4.02–3.92(m,2H),3.89(s,3H),3.81–3.48(m,10H),3.25–3.22(m,1H),3.00–2.90(m,1H),2.89(s,3H),2.80(d,J＝15.5Hz,1H),2.54(qd,J＝13.2,4.8Hz,1H),2.43–2.33(m,2H),2.24–2.06(m,3H).LCMS(ESI)C 44 H 48 F 4 N 9 O 5 + [M+H] + Calculated 858.37, measured 858.4.
Example 137: preparation of 2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03596)
The title compound (GT-03596) (white solid, 37mg, 60% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ8.02(s,1H),7.92(d,J＝6.0Hz,1H),7.72(d,J＝7.7Hz,1H),7.65(d,J＝8.5Hz,1H),7.63–7.55(m,2H),7.40–7.33(m,1H),7.28–7.20(m,1H),7.02(s,1H),6.89(d,J＝7.4Hz,1H),6.48(s,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.62–4.53(m,2H),4.52–4.44(m,2H),4.00–3.92(m,2H),3.89(s,3H),3.82–3.53(m,9H),3.26–3.18(m,2H),3.00–2.90(m,1H),2.89(s,3H),2.84–2.75(m,1H),2.52(qd,J＝13.2,4.6Hz,1H),2.40–2.30(m,2H),2.23–2.16(m,1H),2.16–2.04(m,2H).LCMS(ESI)C 44 H 48 F 4 N 9 O 5 + [M+H] + Calculated 858.37, measured 858.4.
Example 138: preparation of 2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03597)
Referring to scheme 11 and the procedure of example 1, the 2- ((2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-12) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 27 was used to give the title compound (GT-03597) (white solid, 29mg, 45% yield). 1 H NMR(400MHz,MeOD)δ8.02(s,1H),7.73(d,J＝7.5Hz,1H),7.63(s,1H),7.61–7.55(m,2H),7.47(d,J＝9.6Hz,1H),7.40–7.33(m,1H),7.22(d,J＝8.6Hz,1H),6.97(s,1H),6.84(d,J＝8.5Hz,1H),6.48(s,1H),5.15(dd,J＝13.2,5.2Hz,1H),4.63–4.54(m,2H),4.38(s,2H),4.00–3.93(m,2H),3.88(s,3H),3.77–3.40(m,9H),3.18–3.08(m,2H),2.97–2.90(m,1H),2.89(s,3H),2.82–2.75(m,1H),2.55–2.45(m,1H),2.38–2.30(m,2H),2.23–2.14(m,1H),2.12–1.99(m,2H).LCMS(ESI)C 44 H 48 F 4 N 9 O 5 + [M+H] + Calculated 858.37, measured 858.4.
Example 139: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03679)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03679) (white solid, 103mg, 63%) was prepared using 2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-172) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 29. 1 H NMR(400MHz,MeOD)δ8.05(s,1H),7.95–7.87(m,2H),7.80–7.70(m,2H),7.63–7.57(m,2H),7.41–7.33(m,1H),7.31–7.24(m,1H),7.10(s,1H),6.97(d,J＝7.8Hz,1H),6.50(s,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.78(d,J＝13.9Hz,1H),4.60(q,J＝17.5Hz,2H),4.44(d,J＝13.5Hz,1H),4.02–3.93(m,2H),3.90(s,3H),3.83–3.74(m,1H),3.36–3.32(m,2H),2.99–2.90(m,1H),2.89(s,3H),2.83(s,3H),2.82–2.75(m,1H),2.53(qd,J＝13.1,4.4Hz,1H),2.46–2.38(m,2H),2.35–2.26(m,2H),2.23–2.16(m,1H).LCMS(ESI)m/z:C 41 H 44 F 3 N 8 O 5 + [M+H] + Calculated 785.34; found 785.3.
Example 140: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03729)
The title compound (GT-03729) (white solid, 49mg, yield 68.98%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.42(s,1H),11.02(s,1H),10.61(s,1H),10.02(s,1H),8.83(dd,J＝9.6,5.1Hz,1H),8.24–8.09(m,2H),7.78(d,J＝7.8Hz,1H),7.68(d,J＝8.5Hz,1H),7.56(d,J＝3.9Hz,2H),7.34–7.18(m,2H),6.90–6.44(m,3H),5.15(dd,J＝13.2,4.9Hz,1H),4.64(d,J＝12.9Hz,1H),4.51(dd,J＝17.3,11.2Hz,1H),4.38(dd,J＝17.2,9.8Hz,2H),3.94(d,J＝10.0Hz,2H),3.82(s,3H),3.56–3.52(m,1H),2.99–2.85(m,3H),2.76(d,J＝4.5Hz,3H),2.69(s,3H),2.61(d,J＝16.9Hz,1H),2.47–2.35(m,2H),2.26(d,J＝11.6Hz,1H),2.10–1.94(m,3H).LCMS(ESI)C 41 H 43 F 4 N 8 O 5 + [M+H] + Calculated 803.32, measured 803.30.
Example 141: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03730)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03730) (white solid, 55mg, yield 77.42%) was prepared using 2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-172) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 29. 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.02(s,1H),10.61(s,1H),10.03(s,1H),8.90–8.78(m,1H),8.18(s,1H),7.84–7.75(m,3H),7.56(d,J＝3.9Hz,2H),7.33–7.18(m,2H),6.92–6.49(m,3H),5.11(dd,J＝13.2,5.2Hz,1H),4.62–4.51(m,2H),4.44–4.35(m,2H),3.90(d,J＝10.6Hz,2H),3.82(s,3H),3.49(s,1H),2.99–2.86(m,3H),2.75(d,J＝4.5Hz,3H),2.62(s,3H),2.59(s,1H),2.44–2.36(m,2H),2.29(d,J＝11.2Hz,1H),2.02(dd,J＝8.9,3.6Hz,3H).LCMS(ESI)C 41 H 43 F 4 N 8 O 5 + [M+H] + Calculated 803.32, measured 803.30.
Example 142: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03712)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03712) (white solid, 36mg, yield 55.96%) was prepared using 2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) piperidin-4-yl) amino) -N-methylbenzamide (GT-M-171) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) prepared as intermediate example 28. 1 H NMR(400MHz,DMSO)δ12.01(s,1H),11.04(s,1H),10.64(s,1H),10.20(s,1H),9.69(s,1H),8.88(q,J＝4.0Hz,1H),8.17(s,1H),8.06(t,J＝7.0Hz,1H),7.78(d,J＝7.8Hz,1H),7.69(d,J＝7.7Hz,1H),7.55(d,J＝3.9Hz,2H),7.28(dt,J＝8.2,4.2Hz,1H),7.15(d,J＝8.6Hz,1H),6.73(d,J＝1.8Hz,1H),6.58(dd,J＝8.7,1.8Hz,1H),6.50(s,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.64–4.54(m,3H),4.46(d,J＝17.6Hz,1H),3.89(d,J＝9.0Hz,2H),3.80(s,3H),3.55–3.46(m,2H),3.36–3.17(m,4H),2.93(td,J＝13.5,6.8Hz,1H),2.75(d,J＝4.5Hz,3H),2.61(d,J＝16.8Hz,1H),2.44(dd,J＝13.1,4.1Hz,1H),2.06–1.99(m,1H).LCMS(ESI)C 39 H 39 F 4 N 8 O 5 + [M+H] + Calculated 775.29, measured 775.30.
Example 143: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03716)
The title compound (GT-03716) (white solid, 37mg, yield 57.52%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.03(s,1H),10.52(s,1H),8.83–8.71(m,1H),8.11(d,J＝6.2Hz,2H),7.73(dd,J＝22.0,8.1Hz,2H),7.54(d,J＝3.9Hz,2H),7.31–7.17(m,2H),6.72(d,J＝2.0Hz,1H),6.61–6.42(m,2H),5.16(dd,J＝13.3,5.1Hz,1H),4.59–4.47(m,3H),4.38(d,J＝17.4Hz,1H),3.91–3.84(m,2H),3.80(s,3H),3.52–3.46(m,2H),3.24(t,J＝11.1Hz,4H),2.98–2.88(m,1H),2.75(d,J＝4.6Hz,3H),2.61(d,J＝16.7Hz,1H),2.47–2.40(m,1H),2.07–1.98(m,1H).LCMS(ESI)C 39 H 39 F 4 N 8 O 5 + [M+H] + Calculated 775.29, measured 775.30.
Example 144: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03714)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03714) (white solid, 17mg, yield 26.97%) was prepared using 2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) piperidin-4-yl) amino) -N-methylbenzamide (GT-M-171) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 28. 1 H NMR(400MHz,DMSO)δ11.97(s,1H),11.03(s,1H),10.51(s,1H),9.34(s,2H),8.87–8.70(m,1H),8.14(s,1H),7.75(t,J＝6.1Hz,3H),7.54(d,J＝3.9Hz,2H),7.28–7.21(m,2H),6.71(s,1H),6.61–6.48(m,2H),5.11(dd,J＝13.2,5.0Hz,1H),4.54(d,J＝18.1Hz,3H),4.40(d,J＝18.2Hz,1H),3.86(d,J＝11.9Hz,2H),3.80(s,3H),3.41(d,J＝10.2Hz,2H),3.31–3.25(m,2H),3.19(dd,J＝11.1,6.0Hz,2H),2.96–2.89(m,1H),2.75(d,J＝4.5Hz,3H),2.64–2.58(m,1H),2.42(dd,J＝13.4,4.5Hz,1H),2.05–1.98(m,1H).LCMS(ESI)C 39 H 38 F 3 N 8 O 6 + [M+H] + Calculated 771.28, measured 771.30.
Example 145: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03731)
The title compound (GT-03731) (white solid, 48mg, yield 69.11%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.38(s,1H),11.05(s,1H),10.62(s,1H),10.10(s,1H),8.86(d,J＝4.5Hz,1H),8.19(s,1H),7.81(dd,J＝17.1,7.7Hz,2H),7.63(t,J＝6.8Hz,1H),7.56(d,J＝3.9Hz,2H),7.34–7.20(m,2H),6.93–6.51(m,3H),5.18(ddd,J＝30.8,17.7,11.2Hz,2H),4.79(t,J＝17.5Hz,1H),4.63(dd,J＝18.4,5.9Hz,2H),4.51(d,J＝17.4Hz,1H),4.25(dd,J＝14.6,6.1Hz,1H),3.93(d,J＝9.0Hz,2H),3.83(s,3H),3.03–2.89(m,3H),2.75(d,J＝4.5Hz,3H),2.65(dd,J＝9.6,4.2Hz,3H),2.44–2.29(m,3H),2.15–1.96(m,3H).LCMS(ESI)C 41 H 44 F 3 N 8 O 5 + [M+H] + Calculated 785.33, measured 785.30.
Example 146: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03718)
The title compound (GT-03718) (white solid, 34mg, yield 54.12%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.73(s,1H),11.07(s,1H),10.53(s,1H),8.79(d,J＝3.5Hz,1H),8.19–8.02(m,2H),7.85(d,J＝7.4Hz,1H),7.76(d,J＝7.8Hz,1H),7.65(t,J＝7.6Hz,1H),7.55(d,J＝3.9Hz,2H),7.32–7.17(m,2H),6.72(d,J＝1.9Hz,1H),6.64–6.40(m,2H),5.20(dd,J＝13.2,5.1Hz,1H),4.98(d,J＝17.4Hz,1H),4.58–4.42(m,3H),3.88(d,J＝9.0Hz,2H),3.80(s,3H),3.48(d,J＝8.8Hz,2H),3.37–3.28(m,4H),3.01–2.91(m,1H),2.75(d,J＝4.5Hz,3H),2.65(d,J＝16.7Hz,1H),2.39–2.29(m,1H),2.08–2.01(m,1H).LCMS(ESI)C 39 H 40 F 3 N 8 O 5 + [M+H] + Calculated 756.30, measured 756.30.
Example 147: preparation of N- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide (GT-03526)
Referring to scheme 11, step 2 and the procedure of example 1, the N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-152) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 31 gave the title compound (GT-03526) (white solid, 74mg, yield 48%). 1 H NMR(400MHz,MeOD)δ8.23(s,1H),7.93(d,J＝7.8Hz,1H),7.88(s,1H),7.77(d,J＝7.8Hz,1H),7.41–7.15(m,6H),7.11–7.00(m,2H),5.19(dd,J＝13.3,5.1Hz,1H),4.74–4.53(m,7H),3.98–3.84(m,2H),3.66–3.54(m,2H),3.44–3.36(m,2H),3.24(s,3H),3.23–3.12(m,2H),2.94–2.86(m,1H),2.84(s,2H),2.83–2.74(m,1H),2.53(qd,J＝13.1,4.6Hz,1H),2.25–2.15(m,1H).LCMS(ESI)C 38 H 41 FN 9 O 5 S + [M+H] + Calculated 792.29, measured 792.3.
Example 148: preparation of N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide (GT-03705)
Referring to scheme 11, step 2 and the procedure of example 1, N-methyl-N- (3- (((2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-174) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 33 was used to give the title compound (GT-03705) (white solid, 27mg, 38.77% yield). 1 H NMR(400MHz,DMSO)δ11.58(s,1H),11.02(s,1H),10.38(s,1H),9.52(s,1H),8.68(d,J＝2.5Hz,1H),8.60(d,J＝2.3Hz,1H),8.40(s,1H),8.01(d,J＝3.6Hz,1H),7.88(d,J＝7.9Hz,1H),7.81(d,J＝7.8Hz,1H),7.56–7.43(m,2H),7.40–7.31(m,1H),5.15(dd,J＝13.2,5.0Hz,2H),5.00(d,J＝5.0Hz,3H),4.49(dddd,J＝27.9,22.8,12.8,4.5Hz,5H),3.69(dd,J＝16.1,6.8Hz,2H),3.19(d,J＝10.1Hz,7H),2.97–2.89(m,1H),2.62(d,J＝22.0Hz,4H),2.41(ddd,J＝15.5,11.7,4.9Hz,5H),2.04–1.98(m,1H).LCMS(ESI)C 38 H 43 F 3 N 11 O 5 S + [M+H] + Calculated 822.30, measured 822.30.
Example 149: preparation of N- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide (GT-03706)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03706) (white solid, 44mg, yield 64.63%) was prepared using N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-175) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared in intermediate example 34. 1 H NMR(400MHz,DMSO)δ11.00(s,1H),10.31(dd,J＝52.7,34.8Hz,1H),8.69(dd,J＝7.0,2.4Hz,1H),8.59(d,J＝2.3Hz,1H),8.39(d,J＝7.7Hz,1H),8.04–7.87(m,2H),7.85–7.77(m,2H),7.51–7.36(m,2H),7.26–7.19(m,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.99(d,J＝4.9Hz,2H),4.65–4.31(m,8H),3.79–3.65(m,6H),3.22–3.14(m,7H),3.01–2.80(m,2H),2.63–2.58(m,1H),2.47–2.34(m,2H),2.28(dd,J＝9.8,1.9Hz,2H),2.21–2.06(m,2H),2.05–1.81(m,2H).LCMS(ESI)C 41 H 48 F 3 N 12 O 5 S + [M+H] + Calculated 877.35, measured 877.40.
Example 150: preparation of N- (3- (((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide (GT-03742)
Referring to scheme 11, step 2 and the procedure of example 1, N-methyl-N- (3- (((2- ((4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-193) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piper-ide prepared in intermediate example 36 was used The pyridine-2, 6-dione prepared the title compound (GT-03742) (white solid, 53mg, yield 34%). 1 H NMR(400MHz,MeOD)δ8.20(s,1H),7.94(d,J＝7.8Hz,1H),7.86(s,1H),7.75(d,J＝8.0Hz,1H),7.41–7.26(m,7H),7.19(d,J＝7.0Hz,1H),5.19(dd,J＝13.3,5.2Hz,1H),4.70(s,2H),4.59(q,J＝17.5Hz,2H),4.52(s,2H),3.67–3.58(m,2H),3.27–3.19(m,5H),2.99–2.87(m,2H),2.83–2.77(m,4H),2.53(qd,J＝13.2,4.5Hz,1H),2.22–2.02(m,5H).LCMS(ESI)m/z:C 39 H 42 F 3 N 8 O 5 S + [M+H] + Calculated 791.29; found 791.3.
Example 151: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide (GT-03809)
Referring to scheme 11, step 2 and the procedure of example 1, N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] prepared in intermediate example 64 was used]Pyrimidine-3-carboxamide hydrochloride (GT-D-101) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03809) (white solid, 38mg, yield 45%). 1 H NMR(400MHz,MeOD)δ8.54(d,J＝7.9Hz,1H),8.41(s,1H),8.34–8.29(m,1H),7.95(d,J＝7.8Hz,1H),7.82(s,1H),7.73(d,J＝8.0Hz,1H),7.01-6.74(m,1H),6.81(d,J＝8.0Hz,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.61–4.53(m,4H),3.92–3.77(m,8H),3.74–3.66(m,2H),3.54–3.46(m,1H),3.39–3.33(m,2H),3.00–2.86(m,1H),2.85–2.75(m,1H),2.53(dt,J＝13.0,9.0Hz,1H),2.47–2.33(m,4H),2.25–2.15(m,1H).LCMS(ESI)m/z:C 34 H 37 F 2 N 10 O 5 + [M+H] + Calculated 703.29; found 703.3.
Example 152: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide (GT-03810)
Prepared by the method of scheme 11, step 2 and example 1, using intermediate example 64(3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1, 5-a) ]Pyrimidine-3-carboxamide hydrochloride (GT-D-101) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03810) (white solid, 46mg, 53% yield). 1 H NMR(400MHz,MeOD)δ8.54(d,J＝7.9Hz,1H),8.41(s,1H),8.31(s,1H),7.86–7.76(m,2H),7.01(s,1H),6.87(s,1H),6.80(d,J＝8.0Hz,1H),6.74(s,1H),5.20(dd,J＝13.4,5.1Hz,1H),4.73–4.60(m,4H),3.93–3.71(m,10H),3.63–3.53(m,1H),3.45–3.34(m,2H),2.98–2.88(m,1H),2.85–2.75(m,1H),2.60–2.49(m,1H),2.47–2.30(m,4H),2.26–2.15(m,1H).LCMS(ESI)m/z:C 34 H 36 F 3 N 10 O 5 + [M+H] + Calculated 721.28; found 721.3.
Example 153: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide (GT-03811)
The title compound (GT-03811) (white solid, 50mg, 58% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ8.54(d,J＝7.9Hz,1H),8.42(s,1H),8.31(s,1H),7.88(d,J＝5.9Hz,1H),7.71(d,J＝8.5Hz,1H),7.01-6.74(s,1H),6.81(d,J＝8.0Hz,1H),,5.19(dd,J＝13.4,5.1Hz,1H),4.64–4.55(m,4H),3.94–3.70(m,10H),3.66–3.52(m,1H),3.50–3.33(m,2H),2.99–2.87(m,1H),2.83–2.75(m,1H),2.59–2.46(m,1H),2.44–2.28(m,4H),2.26–2.14(m,1H).LCMS(ESI)m/z:C 34 H 36 F 3 N 10 O 5 + [M+H] + Calculated 721.28; found 721.3.
Example 154: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide (GT-03812)
Referring to scheme 11 and the procedure of example 1, N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl prepared in intermediate example 64 was used) -5-morpholinopyrazolo [1,5-a ]]Pyrimidine-3-carboxamide hydrochloride (GT-D-101) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-03812) (white solid, 45mg, yield 52%). 1 H NMR(400MHz,MeOD)δ8.53(d,J＝7.9Hz,1H),8.41(s,1H),8.30(s,1H),7.63(s,1H),7.47(d,J＝9.6Hz,1H),7.00-6.74(m,1H),6.80(d,J＝7.9Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.61–4.52(m,4H),3.96–3.77(m,9H),3.75–3.65(m,2H),3.56–3.46(m,1H),3.40–3.32(m,1H),2.99–2.87(m,1H),2.84–2.75(m,1H),2.61–2.47(m,1H),2.47–2.34(m,4H),2.24–2.13(m,1H).LCMS(ESI)m/z:C 34 H 36 F 3 N 10 O 5 + [M+H] + Calculated 721.28; found 721.3.
Example 155: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide (GT-03816)
The title compound (GT-03816) (white solid, 48mg, yield 57%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.07(s,1H),10.82(s,1H),9.42(s,1H),8.83(d,J＝7.9Hz,1H),8.43(s,1H),8.29(s,1H),7.98(d,J＝7.6Hz,1H),7.85(d,J＝7.4Hz,1H),7.66(t,J＝7.6Hz,1H),7.13(t,J＝53.6Hz,1H),6.91(d,J＝8.0Hz,1H),5.20(dd,J＝13.1,5.1Hz,1H),4.56–4.50(m,2H),4.42(s,2H),3.89–3.67(m,10H),3.57–3.54(m,1H),3.25(d,J＝10.6Hz,2H),3.02–2.91(m,1H),2.72–2.63(m,1H),2.40–2.23(m,5H),2.12–2.03(m,1H).LCMS(ESI)m/z:C 34 H 37 F 2 N 10 O 5 + [M+H] + Calculated 703.29; found 703.3.
Example 156: preparation of 6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide (GT-03553)
Referring to scheme 11, step 2 and the procedure of example 1, 1-isopropyl prepared in example 82 was used as an intermediate-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (piperazin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-7) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione was prepared to give the title compound (GT-03553) (white solid, 116mg, 73% yield). 1 H NMR(400MHz,MeOD)δ8.56(d,J＝2.1Hz,1H),8.44(d,J＝9.4Hz,1H),8.40(s,1H),8.09(s,1H),7.95(d,J＝7.9Hz,1H),7.87(d,J＝11.2Hz,2H),7.77(d,J＝7.6Hz,1H),7.41(d,J＝9.3Hz,1H),6.41(s,1H),5.20(dd,J＝13.5,5.1Hz,1H),5.16–5.08(m,1H),4.59(n,J＝24.0,12.0Hz,6H),3.86–3.32(m,8H),2.99–2.87(m,1H),2.85–2.74(m,3H),2.60–2.46(m,1H),2.34(s,3H),2.24–2.15(m,1H),1.73–1.63(m,2H),1.59(d,J＝6.6Hz,6H),1.05(t,J＝7.3Hz,3H).LCMS(ESI)C 37 H 34 N 5 O 5 + [M+H] + Calculated 784.39, measured 784.4.
Example 157: preparation of 6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide (GT-03743)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03743) (white solid, 37mg, yield 59%) was prepared using 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (methylamino) piperidin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-8) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 83. 1 H NMR(400MHz,MeOD)δ8.59(dd,J＝9.6,2.3Hz,1H),8.46(d,J＝2.2Hz,1H),8.42(s,1H),8.16(s,1H),8.00–7.87(m,3H),7.77(d,J＝7.7Hz,1H),7.61(d,J＝9.6Hz,1H),6.53(s,1H),5.21–5.10(m,2H),4.80–4.73(m,1H),4.66(s,2H),4.59(d,J＝9.2Hz,2H),4.57–4.48(m,2H),4.44(d,J＝12.1Hz,1H),3.94–3.83(m,1H),3.52–3.42(m,2H),2.96–2.84(m,3H),2.82(s,3H),2.81–2.75(m,1H),2.59–2.44(m,3H),2.38(s,3H),2.24–2.10(m,3H),1.70(dq,J＝15.0,7.4Hz,2H),1.60(d,J＝6.6Hz,6H),1.06(t,J＝7.3Hz,3H).LCMS(ESI)m/z:C 46 H 54 N 9 O 5 + [M+H] + Calculated 812.42; found 812.4.
Example 158: preparation of 6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide (GT-03691)
Referring to scheme 11, step 2 and the procedure of example 1, 1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -6- (6- (4- (piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1H-indazole-4-carboxamide (GT-S-9) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 84 gave the title compound (GT-03691) (white solid, 35mg, yield 48.32%). 1 H NMR(400MHz,DMSO)δ11.89(s,1H),11.01(s,1H),9.58(s,3H),8.71–8.61(m,2H),8.37(s,1H),8.27(d,J＝8.2Hz,1H),8.15(s,1H),7.91–7.74(m,4H),7.22(d,J＝8.9Hz,1H),5.93(s,1H),5.14(dd,J＝12.8,5.5Hz,2H),4.63–4.31(m,9H),3.63–3.58(m,4H),3.25–3.15(m,2H),3.05–2.88(m,3H),2.57(dd,J＝28.4,12.2Hz,3H),2.48–2.19(m,6H),2.14(s,3H),2.00(dd,J＝11.7,6.0Hz,1H),1.51(dd,J＝17.0,7.1Hz,9H),0.87(t,J＝7.3Hz,3H).LCMS(ESI)C 49 H 59 N 10 O 5 + [M+H] + Calculated 867.46, measured 867.50.
Example 159: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide (GT-03744)
Referring to scheme 11, step 2 and the procedure of example 1, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (piperazin-1-yl) - [1,1' -biphenyl) prepared in intermediate example 86 was used]The title compound (GT-03744) (white solid, 92mg, 59% yield) was obtained from-3-carboxamide (GT-S-11) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,MeOD)δ8.59(dd,J＝9.6,2.3Hz,1H),8.46(d,J＝2.2Hz,1H),8.42(s,1H),8.16(s,1H),8.00–7.87(m,3H),7.77(d,J＝7.7Hz,1H),7.61(d,J＝9.6Hz,1H),6.53(s,1H),5.21–5.10(m,2H),4.80–4.73(m,1H),4.66(s,2H),4.59(d,J＝9.2Hz,2H),4.57–4.48(m,2H),4.44(d,J＝12.1Hz,1H),3.94–3.83(m,1H),3.52–3.42(m,2H),2.96–2.84(m,3H),2.82(s,3H),2.81–2.75(m,1H),2.59–2.44(m,3H),2.38(s,3H),2.24–2.10(m,3H),1.70(dq,J＝15.0,7.4Hz,2H),1.60(d,J＝6.6Hz,6H),1.06(t,J＝7.3Hz,3H).LCMS(ESI)m/z:C 46 H 54 N 9 O 5 + [M+H] + Calculated 812.42; found 812.4.
Example 160: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide (GT-03710)
Referring to scheme 11, step 2 and the procedure of example 1, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (4- (methylamino) piperidin-1-yl) - [1,1' -biphenyl) prepared in intermediate example 87 was used ]-3-carboxamide (GT-S-12) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione the title compound (GT-03710) was prepared (white solid, 45mg, yield 61.36%). 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.01(s,1H),10.77(s,1H),9.72(s,1H),8.48(s,1H),8.02(s,2H),7.84(dd,J＝33.8,7.6Hz,4H),7.62(dd,J＝9.1,4.2Hz,1H),7.46–7.25(m,2H),5.92(s,1H),5.14(dd,J＝12.8,4.5Hz,1H),4.60(d,J＝12.5Hz,2H),4.54–4.47(m,2H),4.46–4.36(m,3H),4.31(d,J＝3.7Hz,2H),4.07–3.73(m,7H),3.63–3.49(m,3H),3.24(s,2H),3.14–3.05(m,3H),2.92(t,J＝13.1Hz,1H),2.63(s,3H),2.50(s,3H),2.46–2.37(m,3H),2.23(s,3H),2.13(s,3H),2.03(dd,J＝17.3,11.5Hz,2H),1.32(s,3H).LCMS(ESI)C 49 H 60 N 7 O 6 + [M+H] + Calculated 842.45, measured 842.50.
Example 161: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide (GT-03711)
Referring to scheme 11, step 2 and the procedure of example 1, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (4- (piperidin-4-yl) piperazin-1-yl) - [1,1' -biphenyl) prepared in intermediate example 88 was used]The title compound (GT-03711) (white solid, 30mg, yield 42.01%) was obtained from-3-carboxamide (GT-S-13) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione. 1 H NMR(400MHz,DMSO)δ11.78(s,1H),11.44(s,1H),11.01(s,1H),9.53(s,1H),8.47(s,1H),8.11–7.91(m,1H),7.89(s,1H),7.82(d,J＝7.9Hz,1H),7.75(dd,J＝14.3,6.0Hz,2H),7.59(d,J＝7.1Hz,1H),7.10(t,J＝7.3Hz,2H),5.90(s,1H),5.15(dd,J＝13.1,5.0Hz,1H),4.55–4.34(m,7H),3.94(d,J＝11.9Hz,4H),3.87–3.73(m,3H),3.56–3.48(m,5H),3.26(dd,J＝26.8,13.8Hz,7H),3.04–2.88(m,3H),2.61(d,J＝18.8Hz,1H),2.41–2.34(m,3H),2.29(d,J＝11.7Hz,2H),2.23(s,3H),2.12(s,3H),2.03–1.99(m,1H),1.65(dd,J＝42.8,19.4Hz,2H),1.31(d,J＝6.6Hz,6H).LCMS(ESI)C 52 H 65 N 8 O 6 + [M+H] + Calculated 897.49, measured 897.50.
Example 162: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03807)
Referring to scheme 11, step 2 and the procedure of example 1, N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-14) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 89 was used to give the title compound (GT-03807) (white solid, 35mg, 45% yield). 1 H NMR(400MHz,MeOD)δ7.95(d,J＝7.8Hz,1H),7.91(t,J＝4.4Hz,1H),7.85(s,1H),7.75(d,J＝7.7Hz,1H),7.65(s,1H),7.46(d,J＝8.6Hz,1H),7.31(d,J＝8.7Hz,1H),6.88–6.79(m,2H),6.78–6.70(m,1H),5.20(dd,J＝13.2,5.1Hz,1H),4.67–4.53(m,4H),4.20–4.02(m,4H),4.01–3.89(m,2H),3.84–3.72(m,1H),3.70–3.32(m,10H),2.99–2.87(m,1H),2.84–2.75(m,1H),2.62–2.44(m,1H),2.27–2.15(m,1H),2.07–1.97(m,2H),1.66–1.53(m,2H).LCMS(ESI)m/z:C 44 H 45 F 2 N 8 O 5 + [M+H] + Calculated 803.35; found 803.3.
Example 163: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03806)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03806) (white solid, 25mg, 32% yield) was prepared using N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (methylamino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-15) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared in intermediate example 90. 1 H NMR(400MHz,MeOD)δ7.98–7.91(m,2H),7.82(s,1H),7.73(d,J＝7.9Hz,1H),7.65(s,1H),7.47(d,J＝8.7Hz,1H),7.31(d,J＝8.7Hz,1H),6.88–6.80(m,2H),6.78–6.70(m,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.63–4.55(m,2H),4.39(d,J＝12.5Hz,1H),4.25–4.15(m,2H),4.09(s,2H),4.03–3.92(m,2H),3.82–3.75(m,1H),3.73–3.63(m,1H),3.55–3.48(m,2H),3.08–3.00(m,2H),2.95–2.87(m,1H),2.81(s,3H),2.59–2.46(m,1H),2.36–2.25(m,2H),2.25–2.15(m,1H),2.09–1.94(m,5H),1.74–1.62(m,2H).LCMS(ESI)m/z:C 46 H 49 F 2 N 8 O 5 + [M+H] + Calculated 831.38; found 831.4.
Example 164: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03961)
Referring to scheme 11 and the procedure of example 1, N- (5- (3, 5-difluorobenzyl) -1H-indazole prepared in intermediate example 90 was used-3-yl) -4- (4- (methylamino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-15) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03961) (white solid, 27mg, yield 34%). 1 H NMR(400MHz,DMSO)δ12.68(s,1H),11.04(s,1H),10.48(d,J＝26.7Hz,1H),10.15(s,1H),7.97–7.89(m,1H),7.83(d,J＝9.1Hz,1H),7.73(d,J＝7.7Hz,1H),7.48(s,1H),7.41(d,J＝8.6Hz,1H),7.26(d,J＝8.6Hz,1H),7.07–6.94(m,3H),6.32(d,J＝9.0Hz,1H),6.22(s,1H),5.16(dd,J＝13.1,5.0Hz,1H),4.75–4.56(m,2H),4.53–4.32(m,2H),4.13–4.01(m,4H),3.83(d,J＝11.6Hz,2H),3.53–3.46(m,2H),2.98–2.79(m,3H),2.71(s,3H),2.64–2.59(m,1H),2.46–2.41(m,1H),2.31–2.14(m,2H),2.08–1.78(m,6H),1.43–1.30(m,2H).LCMS(ESI)m/z:C 46 H 48 F 3 N 8 O 5 + [M+H] + Calculated 849.37; found 849.4.
Example 165: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03962)
The title compound (GT-03962) (white solid, 30mg, 38% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ12.69(s,1H),11.04(s,1H),10.58(s,1H),10.16(s,1H),8.02(d,J＝5.6Hz,1H),7.84(d,J＝9.0Hz,1H),7.71(d,J＝8.5Hz,1H),7.48(s,1H),7.41(d,J＝8.6Hz,1H),7.26(d,J＝9.7Hz,1H),7.04–6.93(m,3H),6.34(d,J＝8.4Hz,1H),6.24(s,1H),5.16(dd,J＝12.8,4.6Hz,1H),4.67(d,J＝12.6Hz,1H),4.58–4.47(m,1H),4.44–4.28(m,2H),4.15–3.99(m,4H),3.87–3.79(m,3H),3.54–3.42(m,3H),3.00–2.79(m,3H),2.70(s,3H),2.65–2.57(m,1H),2.46–2.39(m,1H),2.34–2.14(m,2H),2.07–1.81(m,5H),1.44–1.31(m,2H).LCMS(ESI)m/z:C 46 H 48 F 3 N 8 O 5 + [M+H] + Calculated 849.37; found 849.4.
Example 166: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03963)
Referring to scheme 11 and the procedure of example 1, the title compound (GT-03963) (white solid, 28mg, yield 36%) was prepared using N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (methylamino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-15) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 90. 1 H NMR(400MHz,DMSO)δ12.67(s,1H),11.03(s,1H),10.62(s,1H),10.14(s,1H),7.83(d,J＝9.0Hz,1H),7.77–7.64(m,2H),7.48(s,1H),7.41(d,J＝8.6Hz,1H),7.26(d,J＝8.7Hz,1H),7.05–6.96(m,3H),6.31(d,J＝9.0Hz,1H),6.20(s,1H),5.12(dd,J＝13.1,5.2Hz,1H),4.67–4.27(m,5H),4.13–3.99(m,5H),3.88–3.79(m,3H),3.54–3.45(m,4H),2.99–2.76(m,4H),2.64(s,3H),2.60–2.56(m,1H),2.44–2.38(m,1H),2.29–2.15(m,2H),2.07–1.73(m,6H),1.42–1.30(m,2H).LCMS(ESI)m/z:C 46 H 48 F 3 N 8 O 5 + [M+H] + Calculated 849.37; found 849.4.
Example 167: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03967)
The title compound (GT-03967) (white solid, 30mg, 39% yield) was obtained by the method of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ12.67(s,1H),11.06(s,1H),10.49(d,J＝60.6Hz,1H),10.14(s,1H),7.94(dd,J＝13.8,7.4Hz,1H),7.89–7.82(m,2H),7.70–7.62(m,1H),7.48(s,1H),7.41(d,J＝8.6Hz,1H),7.29–7.24(m,1H),7.02–6.94(m,3H),6.33(d,J＝8.5Hz,1H),6.23(s,1H),5.28–5.13(m,1H),4.91(d,J＝17.3Hz,1H),4.74–4.51(m,3H),4.25–4.16(m,1H),4.16–4.01(m,5H),3.86–3.79(m,3H),3.49(t,J＝9.9Hz,3H),3.03–2.81(m,4H),2.73–2.61(m,5H),2.42–2.20(m,5H),2.08–1.99(m,2H),1.98–1.82(m,5H),1.44–1.35(m,2H).LCMS(ESI)m/z:C 46 H 49 F 2 N 8 O 5 + [M+H] + Calculated 831.38; found 831.4.
Example 168: preparation of 4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide (GT-03478)
Referring to scheme 11 and the method of example 1, (R) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) is used]-2-yl) methyl) piperazin-1-yl) -N- ((4- ((1- (phenylsulfanyl) -4- (piperazin-1-yl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide (CAS number: 2143096-93-7) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03478) (white solid, 5mg, yield 38%). 1 H NMR(400MHz,MeOD)δ8.30(d,J＝2.0Hz,1H),8.11–8.02(m,1H),7.75(dd,J＝9.0,2.6Hz,2H),7.71–7.62(m,2H),7.40(d,J＝8.4Hz,2H),7.33(d,J＝7.4Hz,2H),7.22–7.09(m,5H),7.04–6.92(m,3H),5.15(dd,J＝13.3,3.0Hz,1H),4.65–4.51(m,2H),4.19–4.02(m,3H),3.89(d,J＝14.4Hz,2H),3.71(s,2H),3.53(d,J＝11.4Hz,2H),3.26–2.76(m,16H),2.56–2.45(m,1H),2.44–2.37(m,2H),2.31–2.15(m,3H),2.11(s,2H),1.58(t,J＝6.4Hz,2H),1.41–1.35(m,1H),1.30(t,J＝7.2Hz,1H),1.08(s,6H).LCMS(ESI)C 61 H 68 ClF 4 N 8 O 8 S 3 + [M+H] + Calculated 1247.39, measured 1247.4.
Example 169: preparation of 4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide (GT-03479)
Referring to scheme 11 and the method of example 1, (R) -4- (4- ((4' -chloro-4, 4-di) is usedMethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl]-2-yl) methyl) piperazin-1-yl) -N- ((4- ((1- (phenylsulfanyl) -4- (piperazin-1-yl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide (CAS number: 2143096-93-7) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-03479) (white solid, 5mg, yield 38%). 1 H NMR(400MHz,MeOD)δ8.31(s,1H),8.10–8.04(m,1H),7.75(dd,J＝9.0,2.6Hz,2H),7.48(s,1H),7.39(d,J＝8.4Hz,2H),7.36–7.29(m,3H),7.22–7.12(m,5H),6.99(d,J＝8.5Hz,3H),5.11(dd,J＝13.3,5.1Hz,1H),4.55–4.46(m,2H),4.20–4.09(m,1H),4.05–3.95(m,2H),3.89(d,J＝13.5Hz,2H),3.53(d,J＝11.7Hz,3H),3.42–3.34(m,3H),3.23–2.86(m,16H),2.81–2.74(m,1H),2.54–2.44(m,1H),2.43–2.37(m,2H),2.35–2.22(m,1H),2.22–2.09(m,4H),1.58(t,J＝6.5Hz,2H),1.31–1.18(m,2H),1.08(s,6H).LCMS(ESI)C 61 H 68 ClF 4 N 8 O 8 S 3 + [M+H] + Calculated 1247.39, measured 1247.4.
Example 170: preparation of 3- (5- ((4- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03958)
The title compound (GT-03958) (white solid, 8mg, yield 10%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.00(s,1H),10.64(s,1H),7.91(d,J＝10.3Hz,1H),7.87–7.76(m,2H),7.18(d,J＝18.7Hz,1H),7.00–6.89(m,2H),6.76(s,1H),5.78–5.64(m,1H),5.15(dd,J＝12.8,5.0Hz,1H),4.55–4.48(m,2H),3.95–3.89(m,3H),3.24–3.09(m,3H),2.97–2.86(m,1H),2.69–2.61(m,2H),2.34–2.23(m,3H),2.06–1.98(m,2H),1.75–1.64(m,3H).LCMS(ESI)m/z:C 38 H 40 F 3 N 7 O 5 + [M+H] + Calculated 731.30; found 731.3.
Example 171: preparation of 6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03827)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03827) (white solid, 54mg, yield 60%) was prepared using 6- (4- (methylamino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-D-77) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5) prepared by intermediate example 52. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),10.86(s,1H),8.28(s,1H),8.16(d,J＝7.7Hz,1H),8.03(d,J＝7.7Hz,1H),7.69–7.62(m,3H),7.54(s,1H),7.47–7.39(m,2H),7.23(s,1H),7.18(t,J＝7.4Hz,1H),7.07(dd,J＝8.6,1.0Hz,2H),7.05–6.99(m,2H),6.90(d,J＝8.8Hz,1H),5.18(dd,J＝12.8,5.4Hz,1H),4.75–4.56(m,3H),4.47–4.36(m,1H),3.66–3.54(m,1H),2.96–2.82(m,3H),2.66–2.62(m,1H),2.59(d,J＝4.4Hz,3H),2.57–2.52(m,1H),2.31–2.19(m,2H),2.13–2.03(m,1H),1.83–1.68(m,2H).LCMS(ESI)m/z:C 46 H 55 N 9 O 10 S 2 + [M+H] + Calculated 958.33; found 958.3.
Example 172: preparation of 6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide (GT-03752)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03752) (white solid, 31mg, yield 46%) was obtained by using 2- (4-phenoxyphenyl) -6- (4- (piperazin-1-yl) piperidin-1-yl) nicotinamide (GT-D-78) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) obtained in intermediate example 53. 1 H NMR(400MHz,MeOD)δ7.97(s,1H),7.92–7.81(m,3H),7.65(d,J＝8.7Hz,2H),7.43–7.36(m,2H),7.16(t,J＝7.5Hz,1H),7.07–6.95(m,5H),5.15(dd,J＝12.6,5.5Hz,1H),4.70–4.59(m,2H),3.95(s,1H),3.65–3.32(m,8H),3.17–3.03(m,3H),2.95–2.81(m,1H),2.80–2.62(m,3H),2.31–2.20(m,2H),2.17–2.11(m,1H),1.86–1.70(m,2H).LCMS(ESI)m/z:C 41 H 42 N 7 O 6 + [M+H] + Calculated 728.32; found, 728.3.
Example 173: preparation of 5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-03739)
Referring to scheme 11, step 2 and the procedure of example 1, 9-cyclopentyl-N prepared by intermediate example 47 was used 8 -phenyl-N 2 - (4- (piperazin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-62) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) gave the title compound (GT-03739) (white solid, 26mg, yield 35.23%). 1 H NMR(400MHz,DMSO)δ11.69(s,1H),11.15(s,1H),10.12(s,1H),9.95(s,1H),8.41(s,1H),8.30(s,1H),8.18(dd,J＝7.7,0.8Hz,1H),8.05(d,J＝7.6Hz,1H),7.82(d,J＝8.0Hz,2H),7.48(d,J＝8.9Hz,2H),7.39(t,J＝8.0Hz,2H),7.11(t,J＝7.4Hz,1H),7.01(d,J＝8.9Hz,2H),5.22–5.12(m,2H),4.61(s,2H),3.77(d,J＝8.9Hz,2H),3.43(d,J＝10.7Hz,2H),3.20(s,4H),2.95–2.87(m,1H),2.67–2.53(m,2H),2.29(dt,J＝16.0,7.9Hz,2H),2.07(dd,J＝8.4,3.7Hz,3H),1.94–1.86(m,2H),1.66–1.58(m,2H).LCMS(ESI)C 40 H 41 N 10 O 4 + [M+H] + Calculated 725.32, measured 725.30.
Example 174: preparation of N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-03938)
Referring to scheme 11, step 2 and the procedure of example 1,3- (imidazo [1,2-b ] prepared in intermediate example 68 is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (piperazin-1-ylmethyl) -3- (trifluoromethyl) phenyl) benzamide hydrochloride (GT-D-109) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS No.: 1312023-72-5) the title compound (GT-03938) was prepared (white solid, 42mg, yield 52%). 1 H NMR(400MHz,DMSO)δ11.13(d,J＝12.2Hz,2H),10.67(s,1H),8.75(dd,J＝4.5,1.5Hz,1H),8.28(dd,J＝9.2,1.5Hz,1H),8.26(s,1H),8.23(d,J＝1.7Hz,1H),8.21–8.13(m,2H),8.11–8.00(m,2H),7.97(dd,J＝8.0,1.8Hz,1H),7.81(d,J＝7.6Hz,1H),7.76(s,1H),7.70(d,J＝7.6Hz,1H),7.57(d,J＝8.2Hz,1H),7.42(dd,J＝9.2,4.5Hz,1H),5.23–5.07(m,2H),4.64–4.36(m,3H),3.43–2.98(m,5H),2.96–2.83(m,3H),2.69–2.65(m,1H),2.62(s,3H),2.59–2.54(m,2H),2.08–2.04(m,1H).LCMS(ESI)m/z:C 42 H 36 F 3 N 8 O 5 + [M+H] + Calculated 789.28; found 789.3.
Example 175: preparation of 5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-03602)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03602) (white solid, 29mg, 36% yield) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-oxide (CAS number 2353496-90-7) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5). 1 H NMR(400MHz,MeOD)δ8.31(s,1H),8.17(s,1H),8.15–8.01(m,3H),7.71(dd,J＝14.5,7.1Hz,1H),7.61(t,J＝7.4Hz,1H),7.51–7.37(m,2H),7.02(s,1H),6.83(d,J＝8.5Hz,1H),5.20(dd,J＝12.6,5.5Hz,1H),4.77–4.46(m,2H),4.05–3.95(m,2H),3.91(s,3H),3.83–3.71(m,1H),3.28–3.17(m,2H),2.95–2.88(m,1H),2.84(s,3H),2.82–2.72(m,2H),2.45–2.37(m,2H),2.35–2.22(m,2H),2.21–2.14(m,1H),1.90(s,3H),1.87(s,3H).LCMS(ESI)C 39 H 43 ClN 8 O 6 P + [M+H] + Calculated 785.27, measured 785.3.
Example 176: preparation of 5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphono) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-03780)
Referring to scheme 11, step 2 and the method of example 1, the methods of (2- ((5-chloro-2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (CAS number: 1197958-90-9) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindole were employed The title compound (GT-03780) (white solid, 16mg, yield 25.40%) was prepared from indoline-1, 3-dione (CAS number 1312023-72-5). 1 H NMR(400MHz,DMSO)δ11.83(s,2H),11.15(s,1H),9.15(s,1H),8.39(s,1H),8.31(s,1H),8.27–8.15(m,2H),8.06(d,J＝7.6Hz,1H),7.61(dd,J＝13.7,7.9Hz,1H),7.39(d,J＝8.4Hz,2H),7.21(t,J＝7.2Hz,1H),6.73(d,J＝1.6Hz,1H),6.55(dd,J＝8.7,1.7Hz,1H),5.20(dd,J＝12.9,5.3Hz,1H),4.62(s,2H),3.87(d,J＝10.9Hz,2H),3.78(s,3H),3.44(d,J＝5.8Hz,2H),3.24(d,J＝9.5Hz,4H),2.95–2.87(m,1H),2.65–2.56(m,2H),2.11–2.03(m,1H),1.80(s,3H),1.77(s,3H).LCMS(ESI)C 37 H 39 ClN 8 O 6 P + [M+H] + Calculated 757.23, measured 757.20.
Example 177: preparation of 8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-03761)
Referring to scheme 11, step 2 and the procedure of example 1, 9-ethyl-6, 6-dimethyl-11-oxo-8- (4- (piperazin-1-yl) piperidin-1-yl) -6, 11-dihydro-5H-benzo [ b ] prepared in intermediate example 45 was used]Carbazole-3-carbonitrile (GT-D-113) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) gave the title compound (GT-03761) (white solid, 60mg, yield 72%), 1 H NMR(400MHz,DMSO)δ12.80(s,1H),11.13(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.00(s,1H),7.82(s,1H),7.76(s,2H),7.36(s,1H),5.17(dd,J＝12.8,5.2Hz,1H),4.09(s,2H),3.45–3.19(m,10H),2.90–2.80(m,4H),2.74–2.67(m,3H),2.26–2.17(m,2H),2.07–2.03(m,2H),1.93–1.86(m,2H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).LCMS(ESI)m/z:C 44 H 46 N 7 O 5 + [M+H] + calculated 752.36; found, 752.4.
Example 178: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03732)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03732) (white solid, 28mg, yield 39.61%) was prepared using 2- ((2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-172) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5) prepared as intermediate example 29. 1 H NMR(400MHz,DMSO)δ11.65(s,1H),11.15(s,1H),10.61(s,1H),10.03(s,1H),8.83(d,J＝3.7Hz,1H),8.37(s,1H),8.26(d,J＝7.8Hz,1H),8.18(s,1H),8.03(d,J＝7.7Hz,1H),7.78(d,J＝7.8Hz,1H),7.57(d,J＝3.9Hz,2H),7.32–7.20(m,2H),6.91–6.53(m,3H),5.19(dd,J＝12.8,5.3Hz,1H),4.70(d,J＝12.2Hz,1H),4.47(dd,J＝12.6,7.1Hz,1H),3.92(d,J＝8.9Hz,2H),3.82(s,3H),3.52(dd,J＝15.7,9.6Hz,2H),3.00–2.85(m,3H),2.76(d,J＝4.5Hz,3H),2.63–2.59(m,3H),2.54(d,J＝8.2Hz,1H),2.39–2.26(m,2H),2.14–1.98(m,3H).LCMS(ESI)C 41 H 42 F 3 N 8 O 6 + [M+H] + Calculated 798.31, measured 798.30.
Example 179: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03713)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03713) (white solid, 20mg, yield 31.25%) was prepared using 2- ((2- ((2-methoxy-4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) piperidin-4-yl) amino) -N-methylbenzamide (GT-M-171) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) prepared as intermediate example 28. 1 H NMR(400MHz,DMSO)δ12.01(s,1H),11.15(s,1H),10.52(s,1H),9.37(s,1H),8.83–8.76(m,1H),8.31(s,1H),8.22–8.10(m,2H),8.05(d,J＝7.7Hz,1H),7.76(d,J＝7.8Hz,1H),7.54(d,J＝3.8Hz,2H),7.25(dd,J＝10.4,6.1Hz,2H),6.71(d,J＝1.6Hz,1H),6.60–6.49(m,2H),5.19(dd,J＝12.9,5.3Hz,1H),4.61(s,2H),3.88(s,2H),3.80(s,3H),3.41(dd,J＝8.9,6.6Hz,3H),3.25(dd,J＝23.3,10.3Hz,4H),2.90(td,J＝14.0,7.4Hz,1H),2.75(d,J＝4.5Hz,3H),2.62(d,J＝17.8Hz,1H),2.12–2.04(m,1H).LCMS(ESI)C 39 H 38 F 3 N 8 O 6 + [M+H] + Calculated 771.28, measured 771.30.
Example 180: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide (GT-03815)
Referring to scheme 11, step 2 and the procedure of example 1, N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] prepared in intermediate example 64 was used]Pyrimidine-3-carboxamide hydrochloride (GT-D-101) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) gave the title compound (GT-03815) (white solid, 50mg, 58% yield). 1 H NMR(400MHz,MeOD)δ8.55(d,J＝7.9Hz,1H),8.43(s,1H),8.32(s,1H),8.11(s,1H),8.07–8.00(m,2H),7.02-6.75(m,1H),6.82(d,J＝8.0Hz,1H),5.19(dd,J＝12.6,5.4Hz,1H),4.83–4.76(m,2H),4.57(s,2H),3.93–3.77(m,9H),3.74–3.58(m,2H),3.43–3.33(m,2H),2.80–2.75(m,3H),2.47–2.29(m,4H),2.21–2.13(m,1H).LCMS(ESI)m/z:C 34 H 35 F 2 N 10 O 6 + [M+H] + Calculated 717.27; found 717.3.
Example 181: preparation of N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-03966)
Referring to scheme 11, step 2 and the procedure of example 1, N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (methylamino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide (GT-S-15) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) prepared the title compound (GT-03966) (white solid, 23mg, 29% yield) using intermediate example 90. 1 H NMR(400MHz,DMSO)δ12.65(s,1H),11.15(s,1H),10.39(s,1H),10.12(s,1H),8.26(s,1H),8.13(d,J＝7.6Hz,1H),8.06(d,J＝7.8Hz,1H),7.87–7.82(m,1H),7.47(s,1H),7.41(d,J＝8.6Hz,1H),7.26(d,J＝8.6Hz,1H),7.06–6.95(m,3H),6.31(d,J＝9.1Hz,1H),6.20(s,1H),5.19(dd,J＝12.8,5.4Hz,1H),4.71(d,J＝10.9Hz,1H),4.58–4.39(m,1H),4.15–3.98(m,4H),3.87–3.79(m,2H),3.73–3.68(m,1H),2.97–2.78(m,5H),2.20(s,2H),2.32–2.04(m,5H),2.04–1.90(m,3H),1.86–1.76(m,1H),1.44–1.30(m,2H).LCMS(ESI)m/z:C 46 H 47 F 2 N 8 O 6 + [M+H] + Calculated 845.36; found 845.4.
Example 182: preparation of 3- (5- ((4- (1- (4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-yl) ethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03633)
Referring to scheme 11, procedure 2 and example 1, 2- (1- (piperazin-1-yl) ethyl) naphtho [2,3-b]Furan-4, 9-dione (CAS number 2226349-69-3) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-03633) (white solid, 53mg, yield 72.57%). 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.11(ddd,J＝6.1,4.3,2.6Hz,2H),7.92–7.85(m,3H),7.76(q,J＝7.8Hz,2H),7.31(s,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.70(s,1H),4.50–4.43(m,3H),4.33(d,J＝17.4Hz,2H),3.49–3.23(m,7H),2.95–2.87(m,1H),2.62–2.57(m,1H),2.41(dd,J＝13.1,4.4Hz,1H),2.02–1.96(m,1H),1.63(d,J＝6.6Hz,3H).LCMS(ESI)C 32 H 31 N 4 O 6 + [M+H] + Calculated 567.61, measured 567.20.
Example 183: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) azetidin-1-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide (GT-03521)
The title compound (GT-03521) was prepared according to the method of scheme 59 (yellow solid, 25mg, yield 30.57%). 1 H NMR(400MHz,DMSO)δ10.98(s,1H),8.60(d,J＝8.2Hz,1H),7.90–7.79(m,2H),7.67(dd,J＝7.8,3.6Hz,1H),7.46(d,J＝13.1Hz,2H),7.41–7.31(m,2H),7.13(dd,J＝8.8,2.4Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.61–4.39(m,4H),4.30(d,J＝17.4Hz,1H),4.16–4.10(m,1H),4.08–3.95(m,3H),3.28(d,J＝8.2Hz,1H),3.22–3.11(m,1H),3.06(dt,J＝23.8,8.0Hz,5H),2.95–2.86(m,1H),2.66–2.55(m,1H),2.45–2.32(m,1H),2.10(d,J＝10.1Hz,2H),2.06–1.94(m,2H),1.87(t,J＝13.4Hz,4H),1.69–1.46(m,5H),1.33–1.19(m,2H).LCMS(ESI)C 41 H 46 ClN 8 O 5 + [M+H] + Calculated 765.32, measured 765.40.
Example 184: preparation of 2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03598)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03598) (white solid, 25mg, 39% yield) was prepared using 2- ((2- ((2-methoxy-4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-M-12) prepared according to intermediate example 27 and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared according to intermediate example 13. 1 H NMR(400MHz,MeOD)δ8.16(s,1H),8.08(d,J＝7.8Hz,1H),8.04(s,1H),7.99(d,J＝7.7Hz,1H),7.73(d,J＝7.6Hz,1H),7.64–7.56(m,2H),7.40–7.34(m,1H),7.30–7.23(m,1H),7.08(s,1H),6.94(d,J＝7.4Hz,1H),6.49(s,1H),5.18(dd,J＝12.6,5.4Hz,1H),4.51(s,2H),3.98–3.92(m,2H),3.89(s,3H),3.77–3.47(m,9H),3.29–3.20(m,2H),2.89(s,3H),2.87–2.82(m,1H),2.80–2.68(m,2H),2.45–2.32(m,2H),2.23–2.08(m,3H).LCMS(ESI)C 44 H 47 F 3 N 9 O 6 + [M+H] + Calculated 854.36, measured 854.4.
Example 185: preparation of 3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04144)
The target compound was prepared according to the procedure of scheme 11 and example 1The product (GT-04144) (white solid, 45mg, yield 52.35%). 1 H NMR(400MHz,DMSO-d 6 )δ11.45(d,J＝29.8Hz,1H),11.05(d,J＝2.7Hz,1H),8.11–7.95(m,1H),7.77–7.67(m,1H),7.04(t,J＝9.2Hz,1H),6.99–6.92(m,2H),6.89(dd,J＝8.5,4.0Hz,2H),6.76(d,J＝8.5Hz,1H),6.69(t,J＝9.1Hz,2H),6.61–6.53(m,3H),6.44(d,J＝8.6Hz,1H),5.17(ddd,J＝14.2,9.6,4.8Hz,1H),4.64–4.46(m,4H),3.51–3.06(m,8H),2.98–2.90(m,1H),2.63(d,J＝16.0Hz,1H),2.48–2.41(m,1H),2.36(d,J＝7.2Hz,2H),2.03(dd,J＝6.2,3.3Hz,1H),0.86(td,J＝7.3,4.6Hz,3H).LCMS(ESI)C 40 H 40 FN 4 O 5 + [M+H] + Calculated 675.29, measured 675.30.
Example 186: preparation of 3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04145)
The title compound (GT-04145) (white solid, 46mg, yield 53.51%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.32(d,J＝34.1Hz,1H),10.94(d,J＝2.7Hz,1H),8.00(dd,J＝15.9,6.1Hz,1H),7.60(t,J＝8.8Hz,1H),6.94(t,J＝8.7Hz,1H),6.89–6.82(m,2H),6.78(dd,J＝8.5,4.3Hz,2H),6.65(d,J＝8.5Hz,1H),6.57(dd,J＝19.2,8.9Hz,2H),6.52–6.43(m,3H),6.33(d,J＝8.6Hz,1H),5.06(dt,J＝13.1,4.7Hz,1H),4.52–4.34(m,3H),4.29(dd,J＝17.4,7.8Hz,1H),3.42–2.91(m,8H),2.83(dd,J＝19.9,8.6Hz,1H),2.54(t,J＝16.5Hz,1H),2.38–2.29(m,1H),2.25(d,J＝7.1Hz,2H),1.94(d,J＝4.4Hz,1H),0.75(td,J＝7.3,4.7Hz,3H).LCMS(ESI)C 40 H 40 FN 4 O 5 + [M+H] + Calculated 675.29, measured 675.30.
Example 187: preparation of 3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04146)
The title compound (GT-04146) (white solid, 56mg, yield 65.15%) was prepared according to the procedure of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.43(d,J＝38.3Hz,1H),11.00–10.86(m,1H),9.26(d,J＝98.2Hz,1H),7.67–7.56(m,2H),6.95(t,J＝9.5Hz,1H),6.87(dd,J＝8.4,6.2Hz,2H),6.80(dd,J＝8.5,4.9Hz,2H),6.67(d,J＝8.5Hz,1H),6.59(dd,J＝19.6,8.9Hz,2H),6.54–6.44(m,3H),6.35(d,J＝8.6Hz,1H),5.09–4.99(m,1H),4.50–4.34(m,4H),3.39–2.95(m,8H),2.90–2.80(m,1H),2.53(d,J＝16.5Hz,1H),2.34–2.20(m,3H),1.98–1.91(m,1H),0.77(td,J＝7.3,4.9Hz,3H).LCMS(ESI)C 40 H 40 FN 4 O 5 + [M+H] + Calculated 675.29, measured 675.30.
Example 188: preparation of 3- (4- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04147)
The title compound (GT-04147) (white solid, 27mg, yield 32.27%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.23(d,J＝37.7Hz,1H),10.96(dd,J＝24.7,7.3Hz,1H),9.11(s,2H),7.95(dd,J＝17.0,7.6Hz,1H),7.77(t,J＝7.4Hz,1H),7.57(dd,J＝16.8,7.7Hz,1H),6.95(t,J＝9.9Hz,1H),6.91–6.84(m,2H),6.80(dd,J＝8.4,5.1Hz,2H),6.67(d,J＝8.5Hz,1H),6.64–6.56(m,2H),6.54–6.46(m,3H),6.35(d,J＝8.6Hz,1H),5.15–5.08(m,1H),4.83(dd,J＝20.2,13.4Hz,1H),4.53–4.45(m,1H),4.41–4.30(m,2H),3.80–3.63(m,2H),3.27–2.95(m,6H),2.86(dd,J＝12.9,4.5Hz,1H),2.58(d,J＝15.2Hz,1H),2.27(dd,J＝7.1,3.5Hz,3H),2.01–1.93(m,1H),0.77(dd,J＝12.5,7.3Hz,3H).LCMS(ESI)C 40 H 41 N 4 O 5 + [M+H] + Calculated 657.30, measured 657.30.
Example 189: preparation of 5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-04148)
The title compound (GT-04148) (white solid, 67mg, yield 78.41%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.27(d,J＝33.2Hz,1H),11.04(s,1H),9.15(s,2H),8.19(d,J＝14.0Hz,1H),8.07(dd,J＝13.9,7.9Hz,1H),8.01–7.92(m,1H),6.95(t,J＝9.2Hz,1H),6.88(dd,J＝15.1,7.6Hz,2H),6.80(dd,J＝8.5,5.1Hz,2H),6.66(d,J＝8.5Hz,1H),6.59(q,J＝8.9Hz,2H),6.53–6.45(m,3H),6.35(d,J＝8.6Hz,1H),5.16–5.09(m,1H),4.52(d,J＝18.6Hz,2H),3.68(dd,J＝51.4,10.4Hz,2H),3.26–2.92(m,6H),2.83(dd,J＝8.6,5.5Hz,1H),2.59–2.51(m,2H),2.34–2.20(m,2H),2.05–2.00(m,1H),0.77(dt,J＝12.1,6.1Hz,3H).LCMS(ESI)C 40 H 39 N 4 O 6 + [M+H] + Calculated 671.28, measured 671.30.
Example 190: preparation of 3- (5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03341)
Referring to the procedure of scheme 12, the title compound (GT-03341) was prepared using 2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenol (CAS number: 1621375-40-3) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) (white solid, 54.00mg, yield 36.31%). 1 H NMR(400MHz,DMSO)δ11.00(s,1H),7.75(ddd,J＝11.5,5.7,2.4Hz,2H),7.66(s,1H),7.55(d,J＝7.9Hz,1H),7.30–7.22(m,2H),5.26(s,2H),5.16–5.11(m,1H),4.47(d,J＝17.5Hz,1H),4.34(d,J＝17.4Hz,1H),3.74–3.66(m,4H),3.44–3.36(m,4H),2.98–2.86(m,1H),2.60(d,J＝17.8Hz,1H),2.40(qd,J＝13.3,4.3Hz,1H),2.05–1.98(m,1H).LCMS(ESI)C 27 H 25 F 2 N 4 O 5 S + [M+H] + Calculated 555.14, measured 555.20.
Example 191: preparation of 3- (5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03808)
Referring to scheme 11, step 2 and the procedure of example 1, 9-cyclopentyl-N prepared by intermediate example 49 was used 8 -phenyl-N 2 - (4- (4- (piperazin-1-yl) piperidin-1-yl) phenyl) -9H-purine-2, 8-diamine (GT-D-68) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03808) (white solid, 14mg, yield 18%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.22(s,1H),8.44(s,1H),7.93(s,1H),7.84–7.73(m,4H),7.68–7.58(m,2H),7.45–7.35(m,4H),7.15(t,J＝7.4Hz,1H),5.24–5.09(m,2H),4.59–4.33(m,5H),3.23–2.82(m,8H),2.68–2.57(m,2H),2.40–2.23(m,5H),2.21–1.87(m,8H),1.71–1.57(m,2H).LCMS(ESI)m/z:C 45 H 52 N 11 O 3 + [M+H] + Calculated 793.42; found, 793.4.
Example 192: preparation of 3- (5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03354)
Referring to the procedure of scheme 12, the title compound (GT-03354) was prepared using 4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-ol (CAS number: 1429757-65-2) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (white solid, 5mg, yield 5%). 1 H NMR(400MHz,MeOD)δ8.67(s,1H),8.05(s,1H),7.87(d,J＝7.9Hz,1H),7.78(s,1H),7.70(d,J＝7.8Hz,1H),7.61–7.56(m,1H),7.53(d,J＝9.9Hz,1H),7.30(s,1H),5.46(s,2H),5.18(dd,J＝13.3,5.2Hz,1H),4.62–4.51(m,2H),4.12(s,3H),2.97–2.87(m,1H),2.84–2.76(m,1H),2.51(qd,J＝13.5,4.9Hz,1H),2.24–2.15(m,1H).LCMS(ESI)C 29 H 23 Cl 2 FN 5 O 5 + [M+H] + Calculated 610.11, found 610.1.
Example 193: preparation of 3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofurane-3-yl) oxy) quinazolin-6-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03353)
Referring to scheme 11, step 2 and the method of example 1, use is made of (S) -N 4 - (3-chloro-4-fluorophenyl) -7- ((tetrahydrofuran-3-yl) oxy) quinazoline-4, 6-diamine (CAS number: 314771-76-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione were prepared to give the title compound (GT-03353) (white solid, 5mg, yield 5%). 1 H NMR(400MHz,MeOD)δ8.55(s,1H),7.83(dd,J＝6.6,2.6Hz,1H),7.76(d,J＝7.8Hz,1H),7.64–7.52(m,3H),7.37–7.27(m,2H),7.13(s,1H),5.39–5.34(m,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.79(s,2H),4.54–4.38(m,2H),4.19(d,J＝10.6Hz,1H),4.14–4.04(m,2H),4.00–3.91(m,1H),2.95–2.83(m,1H),2.82–2.71(m,1H),2.53–2.38(m,2H),2.36–2.27(m,1H),2.21–2.10(m,1H).LCMS(ESI)C 32 H 29 ClFN 6 O 5 + [M+H] + Calculated 631.39, measured 631.2.
Example 194: preparation of 3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03685)
Referring to scheme 11, step 2 and the procedure of example 1, 9-cyclopentyl-N prepared by intermediate example 48 was used 2 - (4- (4- (methylamino) piperidin-1-yl) phenyl) -N 8 phenyl-9H-purine-2, 8-diamine (GT-D-67) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione gave the title compound (GT-03685) (white solid, 16.00mg, yield 22.48%). 1 H NMR(400MHz,DMSO)δ11.61(s,1H),11.03(s,1H),10.44(s,1H),8.48(s,1H),8.06(t,J＝6.9Hz,1H),7.82(d,J＝7.9Hz,2H),7.70(d,J＝7.7Hz,3H),7.66–7.56(m,2H),7.41(t,J＝7.9Hz,2H),7.16(t,J＝7.4Hz,1H),5.31(dd,J＝16.3,7.8Hz,1H),5.16(dd,J＝13.3,5.0Hz,1H),4.62(d,J＝17.8Hz,2H),4.50–4.44(m,2H),3.80–3.65(m,4H),3.43(s,2H),2.97–2.89(m,1H),2.74(s,3H),2.61(d,J＝16.9Hz,1H),2.36(ddd,J＝19.1,16.2,6.1Hz,5H),2.04(ddd,J＝35.3,18.6,4.7Hz,7H),1.67(dd,J＝12.1,6.2Hz,2H).LCMS(ESI)C 42 H 47 N 10 O 3 + [M+H] + Calculated 739.38, measured 739.40.
Example 195: preparation of 3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03924)
Referring to scheme 11, step 2 and the procedure of example 1, prepared using (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-51) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione) prepared as intermediate example 80Target compound (GT-03924) (white solid, 22mg, yield 36.90%). 1 H NMR(400MHz,DMSO)δ13.21(s,1H),11.31(s,1H),11.03(s,1H),9.29(s,1H),8.93(s,2H),8.76(s,1H),8.43(s,1H),8.00(t,J＝9.7Hz,2H),7.86(dd,J＝17.8,7.9Hz,2H),7.37(s,1H),6.87(s,1H),5.15(dd,J＝13.3,4.9Hz,1H),4.69–4.61(m,1H),4.56–4.49(m,1H),4.49–4.32(m,3H),3.80(s,3H),3.40–3.33(m,1H),3.26(ddd,J＝15.8,8.2,4.4Hz,2H),2.98–2.78(m,3H),2.68(s,3H),2.64–2.58(m,1H),2.45(d,J＝13.6Hz,2H),2.42–2.23(m,3H),2.15(s,3H),2.06(s,3H),2.03(s,3H).LCMS(ESI)C 42 H 47 BrN 10 O 5 P + [M+H] + Calculated 881.26, measured 881.30.
Example 196: preparation of 3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03925)
Referring to the procedure of scheme 11, the (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-51) prepared as intermediate example 80 and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) prepared as intermediate example 15 were used to give the title compound (GT-03925) (white solid, 22mg, yield 36.17%). 1 H NMR(400MHz,DMSO)δ13.24(s,1H),11.28(s,1H),11.03(s,1H),9.35(s,1H),8.93(s,2H),8.77(s,1H),8.44(s,1H),8.16–7.91(m,2H),7.71(d,J＝7.7Hz,1H),7.39(s,1H),6.87(s,1H),5.16(dd,J＝12.8,4.3Hz,1H),4.85–4.53(m,3H),4.51–4.30(m,3H),3.81(s,3H),3.52–3.43(m,1H),3.35–3.23(m,2H),2.98–2.81(m,3H),2.75(d,J＝3.5Hz,3H),2.67–2.56(m,2H),2.47–2.35(m,2H),2.27(d,J＝12.5Hz,1H),2.15(s,3H),2.07(s,3H),2.03(s,3H).LCMS(ESI)C 42 H 46 BrFN 10 O 5 P + [M+H] + Calculated 899.25, measured 899.30.
Example 197: preparation of 3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03926)
The title compound (GT-03926) (white solid, 22mg, yield 36.16%) was prepared according to the procedure of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ13.11(s,1H),11.08(d,J＝28.9Hz,2H),9.36–8.95(m,1H),8.92(s,2H),8.87–8.68(m,1H),8.40(s,1H),8.13(dd,J＝5.6,3.1Hz,1H),7.98(d,J＝9.1Hz,1H),7.71(d,J＝7.7Hz,1H),7.38(s,1H),6.84(s,1H),5.16(ddd,J＝12.5,3.7,1.8Hz,1H),4.70(dd,J＝13.1,2.8Hz,1H),4.52(dd,J＝17.7,9.6Hz,1H),4.43–4.36(m,2H),3.81(s,3H),3.59–3.37(m,3H),3.25(dd,J＝15.8,6.6Hz,2H),2.99–2.79(m,3H),2.75(s,3H),2.63(ddd,J＝15.1,4.1,2.4Hz,2H),2.45(dd,J＝13.5,4.5Hz,1H),2.38–2.32(m,1H),2.28–2.22(m,1H),2.14(s,3H),2.06(s,3H),2.02(s,3H).LCMS(ESI)C 42 H 46 BrFN 10 O 5 P + [M+H] + Calculated 899.25, measured 899.30.
Example 198: preparation of 3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03927)
Referring to the procedure of scheme 11, the (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-51) prepared as intermediate example 80 and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 16 were used to give the title compound (GT-03927) (white solid, 26.00mg, yield 42.74%). 1 H NMR(400MHz,DMSO)δ13.13(s,1H),11.44(s,1H),11.02(s,1H),9.11(t,J＝11.9Hz,1H),8.92(s,2H),8.78(d,J＝7.6Hz,1H),8.40(s,1H),7.98(d,J＝9.4Hz,1H),7.81(d,J＝10.6Hz,2H),7.38(s,1H),6.85(s,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.59(ddd,J＝25.9,13.3,6.4Hz,2H),4.46–4.38(m,2H),3.80(s,3H),3.50–3.33(m,2H),3.24(dd,J＝13.5,7.7Hz,2H),2.91(ddd,J＝33.4,19.5,12.5Hz,3H),2.69(s,3H),2.65–2.55(m,2H),2.45–2.24(m,4H),2.14(s,3H),2.06(s,3H),2.03(s,3H).LCMS(ESI)C 42 H 46 BrFN 10 O 5 P + [M+H] + Calculated 899.25, measured 899.30.
Example 199: preparation of 3- (4- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03928)
The title compound (GT-03928) (white solid, 20.00mg, yield 33.55%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ13.24(s,1H),11.16(d,J＝29.2Hz,1H),11.07(s,1H),9.35(dt,J＝14.9,11.4Hz,1H),8.93(s,2H),8.77(dd,J＝12.9,6.6Hz,1H),8.44(s,1H),8.20–7.89(m,2H),7.85(d,J＝7.6Hz,1H),7.68–7.62(m,1H),7.39(s,1H),6.88(s,1H),5.24–5.16(m,1H),4.81–4.52(m,3H),4.30–4.20(m,2H),3.82(s,3H),3.65–3.39(m,2H),3.34–3.23(m,2H),3.01–2.80(m,3H),2.70(dd,J＝12.3,4.7Hz,3H),2.64–2.53(m,1H),2.46–2.20(m,4H),2.15(s,3H),2.07(s,3H),2.03(s,3H).LCMS(ESI)C 42 H 47 BrN 10 O 5 P + [M+H] + Calculated 881.26, measured 881.30.
Example 200: preparation of 5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxo-3-yl) isoindoline-1, 3-dione (GT-03929)
Referring to scheme 11, step 2 and the procedure of example 1, the (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-51) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) prepared as intermediate example 80 gave the title compound (GT-03929) (white solid, 20.00mg, yield 33.03%). 1 H NMR(400MHz,DMSO)δ13.05(s,1H),11.31(s,1H),11.15(s,1H),9.02–8.87(m,3H),8.86–8.73(m,1H),8.37(d,J＝4.6Hz,2H),8.25(d,J＝7.7Hz,1H),8.05(d,J＝7.6Hz,1H),7.97(d,J＝9.1Hz,1H),7.38(s,1H),6.83(s,1H),5.20(dd,J＝12.9,5.3Hz,1H),4.80–4.68(m,1H),4.50(ddd,J＝8.1,5.8,1.3Hz,1H),3.80(s,3H),3.41(dd,J＝18.5,10.1Hz,2H),3.24(s,2H),2.96–2.78(m,3H),2.68(d,J＝4.2Hz,3H),2.59(ddd,J＝13.0,5.6,4.7Hz,4H),2.35–2.28(m,2H),2.14(s,3H),2.06(s,3H),2.02(s,3H).LCMS(ESI)C 42 H 45 BrN 10 O 6 P + [M+H] + Calculated 895.24, measured 895.20.
Example 201: preparation of 3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03858)
Referring to the procedure of scheme 11, 9-cyclopentyl-N prepared by intermediate example 48 2 - (4- (4- (methylamino) piperidin-1-yl) phenyl) -N 8 phenyl-9H-purine-2, 8-diamine (GT-D-67) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) obtained in intermediate example 15 gave the title compound (GT-03858) (white solid, 28mg, yield 38.40%). 1 H NMR(400MHz,DMSO)δ11.61(s,1H),11.03(s,1H),10.44(s,1H),8.48(s,1H),8.06(t,J＝6.9Hz,1H),7.82(d,J＝7.9Hz,2H),7.70(d,J＝7.7Hz,3H),7.66–7.56(m,2H),7.41(t,J＝7.9Hz,2H),7.16(t,J＝7.4Hz,1H),5.31(dd,J＝16.3,7.8Hz,1H),5.16(dd,J＝13.3,5.0Hz,1H),4.62(d,J＝17.8Hz,2H),4.50–4.44(m,2H),3.80–3.65(m,4H),3.43(s,2H),2.97–2.89(m,1H),2.74(s,3H),2.61(d,J＝16.9Hz,1H),2.36(ddd,J＝19.1,16.2,6.1Hz,5H),2.04(ddd,J＝35.3,18.6,4.7Hz,6H),1.67(dd,J＝12.1,6.2Hz,2H).LCMS(ESI)C 42 H 46 FN 10 O 3 + [M+H] + Calculated 757.37, measured 757.40.
Example 202: preparation of 3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03859)
The title compound (GT-03859) (white solid, 20.00mg, yield 27.43%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.49(s,1H),11.03(s,1H),10.39(s,1H),8.47(s,1H),8.14(d,J＝5.4Hz,1H),7.81(d,J＝7.9Hz,2H),7.69(d,J＝8.5Hz,3H),7.62–7.46(m,2H),7.41(t,J＝7.8Hz,2H),7.15(t,J＝7.4Hz,1H),5.29(dd,J＝16.6,8.2Hz,1H),5.15(dd,J＝13.0,4.9Hz,1H),4.65(d,J＝11.9Hz,1H),4.45–4.34(m,3H),3.79(d,J＝7.9Hz,2H),3.66(s,2H),3.39(s,2H),2.95–2.88(m,1H),2.74(s,3H),2.61(dd,J＝15.8,1.0Hz,1H),2.45–2.31(m,5H),2.15–1.87(m,6H),1.71–1.62(m,2H).LCMS(ESI)C 42 H 46 FN 10 O 3 + [M+H] + Calculated 757.37, measured 757.40.
Example 203: preparation of 3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03860)
Referring to the procedure of scheme 11, 9-cyclopentyl-N prepared by intermediate example 48 2 - (4- (4- (methylamino) piperidin-1-yl) phenyl) -N 8 phenyl-9H-purine-2, 8-diamine (GT-D-67) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) obtained in intermediate example 16 gave the title compound (GT-03860) (white solid, 20mg, yield 27.43%). 1 H NMR(400MHz,DMSO)δ11.75(s,1H),11.03(s,1H),10.40(s,1H),8.48(s,1H),7.85–7.78(m,4H),7.71(d,J＝7.9Hz,2H),7.63(s,2H),7.42(t,J＝7.7Hz,2H),7.17(t,J＝7.5Hz,1H),5.27(dd,J＝17.3,8.8Hz,1H),5.11(dd,J＝13.1,5.0Hz,1H),4.57–4.44(m,4H),3.75(d,J＝8.7Hz,2H),3.66–3.57(m,2H),3.50–3.37(m,2H),2.95–2.88(m,1H),2.69–2.58(m,4H),2.44–2.31(m,5H),2.14–1.91(m,6H),1.67(dd,J＝12.6,6.6Hz,2H).LCMS(ESI)C 42 H 46 FN 10 O 3 + [M+H] + Calculated 757.37, measured 757.40.
Example 204: preparation of 3- (4- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03861)
The title compound (GT-03861) (white solid) was obtained by the method described in scheme 11, step 2 and example 123mg, yield 32.32%). 1 H NMR(400MHz,DMSO)δ11.62(s,1H),11.06(s,1H),10.58(s,1H),8.50(s,1H),8.09(dd,J＝28.8,7.4Hz,1H),7.87–7.71(m,7H),7.64(t,J＝7.5Hz,1H),7.42(t,J＝7.7Hz,2H),7.18(t,J＝7.3Hz,1H),5.39–5.32(m,1H),5.19(dd,J＝12.6,8.0Hz,1H),4.63–4.57(m,3H),4.36(dd,J＝11.0,5.1Hz,2H),3.86–3.73(m,3H),3.61(s,2H),2.95(t,J＝15.0Hz,1H),2.63(dd,J＝34.2,16.1Hz,6H),2.39–2.26(m,3H),2.16–1.83(m,6H),1.70–1.59(m,2H).LCMS(ESI)C 42 H 47 N 10 O 3 + [M+H] + Calculated 739.38, measured 739.40.
Example 205: preparation of 5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-03862)
Referring to scheme 11, step 2 and the procedure of example 1, 9-cyclopentyl-N prepared by intermediate example 48 was used 2 - (4- (4- (methylamino) piperidin-1-yl) phenyl) -N 8 phenyl-9H-purine-2, 8-diamine (GT-D-67) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) gave the title compound (GT-03862) (white solid, 25mg, yield 34.47%). 1 H NMR(400MHz,DMSO)δ11.74(s,1H),11.16(s,1H),10.35(s,1H),8.47(s,1H),8.39(s,1H),8.28(d,J＝7.6Hz,1H),8.03(d,J＝7.7Hz,1H),7.82(d,J＝7.9Hz,2H),7.68(d,J＝7.3Hz,2H),7.55(s,2H),7.40(t,J＝7.8Hz,2H),7.14(t,J＝7.3Hz,1H),5.29–5.17(m,2H),4.69(d,J＝12.3Hz,1H),4.53(d,J＝10.9Hz,1H),3.77(s,3H),3.64(d,J＝3.9Hz,1H),3.35(s,1H),2.93–2.86(m,1H),2.66(s,3H),2.58(d,J＝10.5Hz,1H),2.34(dd,J＝11.2,7.3Hz,3H),2.13–2.06(m,3H),1.96(d,J＝14.1Hz,2H),1.69–1.62(m,2H).LCMS(ESI)C 42 H 45 N 10 O 4 + [M+H] + Calculated 753.35, measured 753.40.
Example 206: preparation of 3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03907)
Referring to scheme 11, step 2 and the procedure of example 1, the (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-50) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione prepared as intermediate example 79 gave the title compound (GT-03907) (white solid, 40.00mg, yield 66.67%). 1 H NMR(400MHz,DMSO)δ12.86(s,1H),11.27(s,1H),11.03(s,1H),8.88(dd,J＝10.2,1.7Hz,3H),8.57(s,1H),8.32(s,1H),7.96(d,J＝10.0Hz,2H),7.88–7.80(m,2H),7.46(s,1H),6.72(s,1H),5.16(dd,J＝13.2,5.1Hz,1H),4.53(d,J＝17.7Hz,3H),4.40(d,J＝17.7Hz,1H),3.80(s,3H),3.41(d,J＝10.9Hz,3H),3.31–3.16(m,6H),2.98–2.88(m,1H),2.61(d,J＝17.1Hz,1H),2.47–2.39(m,1H),2.11(s,3H),2.05(s,3H),2.01(s,3H).LCMS(ESI)C 40 H 43 BrN 10 O 5 P + [M+H] + Calculated 853.23, measured 853.20.
Example 207: preparation of 3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03908)
Referring to the procedure of scheme 11, the title compound (GT-03908) (white solid, 40.00mg, yield 65.30%) was prepared using (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-xide (GT-S-50) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) prepared as intermediate example 79. 1 H NMR(400MHz,DMSO)δ12.85(s,1H),11.20(s,1H),11.03(s,1H),8.93–8.79(m,3H),8.54(s,1H),8.32(s,1H),8.04–7.90(m,2H),7.73(d,J＝7.7Hz,1H),7.47(s,1H),6.72(s,1H),5.16(dd,J＝13.3,5.0Hz,1H),4.63(d,J＝17.8Hz,3H),4.48(d,J＝17.6Hz,1H),3.80(s,3H),3.43–3.27(m,5H),3.20(s,4H),2.98–2.89(m,1H),2.62(d,J＝17.7Hz,1H),2.44(dd,J＝13.7,5.1Hz,1H),2.11(s,3H),2.05(s,3H),2.01(s,3H).LCMS(ESI)C 40 H 42 BrFN 10 O 5 P + [M+H] + Calculated value 871.22, actual measurementValue 871.20.
Example 208: preparation of 3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03909)
The title compound (GT-03909) (white solid, 40.00mg, yield 65.30%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ12.84(s,1H),11.15(s,1H),11.04(s,1H),8.87(dt,J＝10.8,5.4Hz,3H),8.53(s,1H),8.32(s,1H),8.09(d,J＝5.9Hz,1H),7.96(d,J＝9.4Hz,1H),7.72(d,J＝8.5Hz,1H),7.46(s,1H),6.71(s,1H),5.16(dd,J＝13.4,4.9Hz,1H),4.63–4.47(m,3H),4.39(d,J＝17.4Hz,1H),3.80(s,3H),3.34(dd,J＝15.5,6.9Hz,4H),3.20(d,J＝0.9Hz,5H),2.97–2.89(m,1H),2.67–2.58(m,1H),2.47–2.43(m,1H),2.11(s,3H),2.05(s,3H),2.01(s,3H).LCMS(ESI)C 40 H 42 BrFN 10 O 5 P + [M+H] + Calculated 871.22, measured 871.20.
Example 209: preparation of 3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03910)
Referring to the procedure of scheme 11, the title compound (GT-03910) (white solid, 40.00mg, yield 65.30%) was prepared using (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-xide (GT-S-50) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 79. 1 H NMR(400MHz,DMSO)δ12.87(s,1H),11.42(s,1H),11.02(s,1H),8.91–8.75(m,3H),8.58(s,1H),8.33(s,1H),7.97(d,J＝9.4Hz,1H),7.73(d,J＝13.7Hz,2H),7.47(s,1H),6.73(s,1H),5.12(dd,J＝13.2,5.0Hz,1H),4.64–4.51(m,3H),4.42(d,J＝18.1Hz,1H),3.81(s,3H),3.43(d,J＝10.4Hz,3H),3.29–3.15(m,6H),2.97–2.88(m,1H),2.61(dd,J＝16.7,1.7Hz,1H),2.42(dd,J＝13.0,4.8Hz,1H),2.11(s,3H),2.05(s,3H),2.02(s,3H).LCMS(ESI)C 40 H 42 BrFN 10 O 5 P + [M+H] + Calculated 871.22, measured 871.20.
Example 210: preparation of 3- (4- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03911)
The title compound (GT-03911) (white solid, 40.00mg, 66.67% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ12.97(s,1H),11.43(s,1H),11.09(s,1H),8.86(ddd,J＝19.8,11.9,5.7Hz,4H),8.36(s,1H),8.12(d,J＝7.6Hz,1H),7.97(d,J＝9.3Hz,1H),7.85(d,J＝7.5Hz,1H),7.66(t,J＝7.6Hz,1H),7.46(s,1H),6.72(s,1H),5.21(dd,J＝13.0,5.0Hz,1H),4.93(d,J＝17.7Hz,1H),4.61–4.45(m,3H),3.80(s,3H),3.50–3.32(m,5H),3.24(dd,J＝28.3,11.8Hz,4H),3.02–2.91(m,1H),2.66(dd,J＝15.5,1.5Hz,1H),2.41–2.30(m,1H),2.13(s,3H),2.05(s,3H),2.02(s,3H).LCMS(ESI)C 40 H 43 BrN 10 O 5 P + [M+H] + Calculated 853.23, measured 853.20.
Example 211: preparation of 5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxo-3-yl) isoindoline-1, 3-dione (GT-03912)
Referring to scheme 11, step 2 and the procedure of example 1, the (6- ((5-bromo-2- ((2-methoxy-5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphino-oxide (GT-S-50) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) prepared as intermediate example 79 gave the title compound (GT-03912) (white solid, 40.00mg, yield 65.60%). 1 H NMR(400MHz,DMSO)δ12.83(s,1H),11.42(s,1H),11.15(s,1H),9.04–8.80(m,3H),8.50(s,1H),8.31(s,2H),8.19(d,J＝7.8Hz,1H),8.06(d,J＝7.6Hz,1H),7.96(d,J＝9.5Hz,1H),7.47(s,1H),6.73(s,1H),5.20(dd,J＝12.9,5.3Hz,1H),4.64(s,2H),3.80(s,3H),3.38–3.10(m,8H),2.96–2.84(m,1H),2.66–2.53(m,3H),2.11(s,3H),2.05(s,3H),2.01(s,3H).LCMS(ESI)C 40 H 41 BrN 10 O 6 P + [M+H] + Calculated 867.21, measured 867.20.
Example 212: preparation of N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) - [1,4' -bipiperidine ] -4-carboxamide (GT-03483)
Referring to scheme 11, step 2 and the procedure of example 1, N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) - [1,4' -bipiperidine was used]The title compound (GT-03483) was prepared from-4-carboxamide (CAS number 2791384-17-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) (white solid, 20.00mg, yield 64.41%). 1 H NMR(400MHz,DMSO)δ12.45(s,1H),9.22(s,1H),7.88–7.81(m,2H),7.78–7.73(m,1H),7.40–7.37(m,1H),7.25–7.12(m,1H),6.76–6.71(m,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.51(d,J＝17.3Hz,1H),4.44–4.35(m,3H),4.07(d,J＝11.9Hz,2H),2.98(td,J＝13.3,7.1Hz,5H),2.81–2.74(m,1H),2.68–2.57(m,2H),2.45–2.39(m,1H),2.34–2.15(m,7H),2.09–1.94(m,6H),1.18(d,J＝2.4Hz,9H).LCMS(ESI)C 36 H 46 N 7 O 5 S 2 + [M+H] + Calculated 720.29, measured 720.30.
Example 213: preparation of 3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04044)
The title compound (GT-04044) (white solid, 51mg, yield 63.53%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.17(d,J＝53.3Hz,1H),11.00(s,1H),8.37–8.28(m,1H),7.96(d,J＝7.4Hz,1H),7.90(s,1H),7.80(q,J＝7.8Hz,2H),7.72–7.48(m,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.57–4.27(m,4H),3.85(s,3H),3.49–3.19(m,3H),3.13–2.85(m,5H),2.61(d,J＝17.3Hz,1H),2.46–2.35(m,1H),2.16–1.85(m,5H),0.92(td,J＝12.7,7.7Hz,1H),0.40–0.29(m,2H),0.09(dt,J＝9.2,4.2Hz,2H).LCMS(ESI)C 31 H 36 ClN 8 O 3 + [M+H] + Calculated 603.25, measured 603.30.
Example 214: preparation of 3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04045)
The title compound (GT-04044) (white solid, 62mg, yield 74.99%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.34(d,J＝65.2Hz,1H),11.02(s,1H),8.39–8.27(m,1H),8.10–7.83(m,2H),7.68(d,J＝7.7Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.64–4.54(m,1H),4.51–4.36(m,3H),3.85(s,3H),3.65–3.20(m,3H),3.28–2.75(m,5H),2.61(d,J＝17.0Hz,1H),2.49–2.37(m,1H),2.21–1.85(m,5H),0.92(td,J＝12.8,7.0Hz,1H),0.40–0.27(m,2H),0.09(dd,J＝12.5,7.7Hz,2H).LCMS(ESI)C 31 H 35 FClN 8 O 3 + [M+H] + Calculated 621.24, measured 621.30.
Example 215: preparation of 3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04046)
The title compound (GT-04046) (white solid, 57mg, 68.95% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.43(d,J＝54.9Hz,1H),11.02(s,1H),8.39–8.28(m,1H),8.16–8.07(m,1H),7.97(d,J＝8.4Hz,1H),7.66(d,J＝8.5Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.53–4.32(m,4H),3.90(dd,J＝13.9,7.1Hz,1H),3.85(s,3H),3.66–3.16(m,3H),3.13–2.98(m,3H),2.95–2.84(m,1H),2.61(d,J＝17.3Hz,1H),2.47–2.32(m,1H),2.23–1.86(m,5H),1.02–0.81(m,1H),0.41–0.27(m,2H),0.09(dd,J＝12.0,7.2Hz,2H).LCMS(ESI)C 31 H 35 FClN 8 O 3 + [M+H] + Calculated 621.24, measured 621.30.
Example 216: preparation of 3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04047)
The title compound (GT-04047) (white solid, 64mg, yield 77.41%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.47(d,J＝48.5Hz,1H),11.02(s,1H),8.33(d,J＝16.9Hz,1H),7.96(s,1H),7.72(t,J＝4.8Hz,2H),5.10(dd,J＝13.2,5.0Hz,1H),4.46(q,J＝17.9Hz,4H),3.85(s,4H),3.55–3.08(m,3H),3.05–2.86(m,4H),2.60(d,J＝17.0Hz,1H),2.41(qd,J＝13.1,4.3Hz,1H),2.21–1.87(m,5H),1.02–0.81(m,1H),0.34(tt,J＝5.8,5.3Hz,2H),0.15–0.02(m,2H).LCMS(ESI)C 31 H 35 FClN 8 O 3 + [M+H] + Calculated 621.24, measured 621.30.
Example 217: preparation of 3- (4- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04048)
The title compound (GT-04048) (white solid, 63mg, yield 78.48%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(500MHz,DMSO)δ11.03(dd,J＝50.2,14.8Hz,2H),8.39–8.29(m,1H),7.99(t,J＝14.1Hz,1H),7.84(d,J＝7.5Hz,1H),7.72–7.50(m,2H),5.24–5.13(m,1H),4.85(dd,J＝17.4,8.8Hz,1H),4.59–4.47(m,1H),4.44–4.27(m,2H),3.86(s,4H),3.48–2.90(m,7H),2.71–2.60(m,1H),2.34(tt,J＝13.2,6.5Hz,1H),2.06(ddd,J＝71.1,48.4,13.3Hz,5H),0.91(tdt,J＝20.5,13.8,6.8Hz,1H),0.47–0.27(m,2H),0.09(t,J＝14.4Hz,2H).LCMS(ESI)C 31 H 36 ClN 8 O 3 + [M+H] + Calculated 603.25, measured 603.30.
Example 218: preparation of 5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-04049)
The title compound (GT-04049) (white solid, 55mg, yield 66.96%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.35(s,1H),11.14(s,1H),8.31(t,J＝14.5Hz,2H),8.16(d,J＝7.7Hz,1H),8.02(d,J＝7.7Hz,1H),7.94(d,J＝8.1Hz,1H),5.19(dd,J＝12.8,5.4Hz,1H),4.51(d,J＝4.0Hz,2H),3.85(s,3H),3.62–3.11(m,3H),3.06–2.87(m,4H),2.70–2.50(m,3H),2.10(dd,J＝28.4,23.1Hz,3H),1.93(dd,J＝23.9,10.5Hz,2H),1.02–0.86(m,1H),0.35(dt,J＝12.0,6.6Hz,2H),0.09(dd,J＝10.2,5.8Hz,2H).LCMS(ESI)C 31 H 34 ClN 8 O 4 + [M+H] + Calculated 617.23, measured 617.30.
Example 219: preparation of 4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04060)
Referring to scheme 11, step 2 and the procedure of example 1, 4- (((5 ' -chloro-2 ' - (piperidin-4-ylamino) - [2,4' -bipyridine) prepared in intermediate example 38 was used]-6-yl) amino) methyl-tetrahydro-2H-pyran-4-carbonitrile (GT-M-159) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-04060) (white solid, 56mg, yield 86.90%). 1 H NMR(400MHz,DMSO)δ11.32(d,J＝52.7Hz,1H),11.02(s,1H),8.13(d,J＝17.6Hz,1H),7.92(d,J＝6.1Hz,1H),7.85–7.75(m,2H),7.69(d,J＝6.9Hz,1H),7.34–6.61(m,3H),5.15(dd,J＝13.2,5.0Hz,1H),4.55–4.39(m,4H),3.97–3.87(m,3H),3.72(d,J＝7.8Hz,2H),3.45(dd,J＝13.9,8.7Hz,4H),3.12(dt,J＝21.8,10.3Hz,2H),2.98–2.86(m,1H),2.63(t,J＝15.7Hz,1H),2.47–2.35(m,1H),2.15(d,J＝11.6Hz,2H),2.07–1.92(m,3H),1.87(d,J＝13.1Hz,2H),1.69(tt,J＝13.6,6.8Hz,2H).LCMS(ESI)C 36 H 40 ClN 8 O 4 + [M+H] + Calculated 683.28, measured 683.30.
Example 220: preparation of 4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04061)
Referring to the procedure of scheme 11, 4- (((5 ' -chloro-2 ' - (piperidin-4-ylamino) - [2,4' -bipyridine) obtained in intermediate example 38 was used]-6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile(GT-M-159) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-04061) (white solid, 55mg, yield 83.17%). 1 H NMR(400MHz,DMSO)δ11.37(d,J＝53.9Hz,1H),11.04(s,1H),8.13(d,J＝16.2Hz,1H),8.05–7.95(m,1H),7.76–7.60(m,2H),7.33–6.74(m,3H),5.15(dt,J＝16.0,7.9Hz,1H),4.60–4.45(m,4H),3.99–3.83(m,3H),3.73(s,2H),3.58–3.39(m,4H),3.24(d,J＝89.1Hz,2H),2.99–2.85(m,1H),2.62(d,J＝16.8Hz,1H),2.48–2.31(m,1H),2.26–2.08(m,2H),2.08–1.92(m,3H),1.87(d,J＝13.3Hz,2H),1.69(td,J＝13.5,4.3Hz,2H).LCMS(ESI)C 36 H 39 FClN 8 O 4 + [M+H] + Calculated 701.27, measured 701.30.
Example 221: preparation of 4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04062)
The title compound (GT-04062) (white solid, 54mg, yield 81.65%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.41(d,J＝54.2Hz,1H),11.08(d,J＝8.4Hz,1H),8.18(t,J＝11.8Hz,2H),7.73(dd,J＝8.4,3.5Hz,2H),7.32–6.66(m,3H),5.20(dt,J＝15.1,7.6Hz,1H),4.53(dd,J＝31.5,20.0Hz,4H),4.00–3.89(m,3H),3.78(s,2H),3.52(dd,J＝22.7,11.8Hz,4H),3.20(d,J＝9.2Hz,2H),3.04–2.92(m,1H),2.70(dd,J＝24.1,9.3Hz,1H),2.47(ddd,J＝26.0,17.5,6.6Hz,1H),2.33–2.14(m,2H),2.06(dd,J＝21.0,9.0Hz,3H),1.93(d,J＝13.2Hz,2H),1.74(td,J＝13.6,4.4Hz,2H).LCMS(ESI)C 36 H 39 FClN 8 O 4 + [M+H] + Calculated 701.27, measured 701.30.
Example 222: preparation of 4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04063)
Referring to the procedure of scheme 11, 4- (((5 '-chloro-2' - (piperidin-4-ylamino) - [ 2) obtained in intermediate example 38 was used4' -bipyridine]-6-yl) amino-methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-159) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-04063) (white solid, 57mg, 86.19% yield). 1 H NMR(400MHz,DMSO)δ11.56(d,J＝39.7Hz,1H),11.09(s,1H),8.19(d,J＝18.5Hz,1H),7.86–7.67(m,3H),7.36–6.82(m,3H),5.17(dd,J＝13.2,5.0Hz,1H),4.62–4.49(m,4H),3.96(dd,J＝10.5,3.7Hz,3H),3.79(d,J＝6.8Hz,2H),3.51(t,J＝11.2Hz,4H),3.19(dd,J＝46.8,36.5Hz,2H),3.04–2.85(m,1H),2.69(t,J＝17.8Hz,1H),2.53–2.38(m,1H),2.30–2.15(m,2H),2.13–1.99(m,3H),1.98–1.86(m,2H),1.74(td,J＝13.5,4.3Hz,2H).LCMS(ESI)C 36 H 39 FClN 8 O 4 + [M+H] + Calculated 701.27, measured 701.30.
Example 223: preparation of 4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04064)
The title compound (GT-04064) (white solid, 56mg, 86.90% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.37(d,J＝32.1Hz,1H),11.12(d,J＝10.0Hz,1H),8.15(dd,J＝34.4,12.0Hz,2H),7.88(dd,J＝7.2,3.8Hz,1H),7.71(dd,J＝21.0,13.4Hz,2H),7.08(dd,J＝108.1,79.7Hz,3H),5.24(dt,J＝13.2,6.6Hz,1H),5.06–4.95(m,1H),4.59(d,J＝17.5Hz,1H),4.46(t,J＝9.1Hz,2H),4.04–3.93(m,3H),3.78(s,2H),3.51(t,J＝11.2Hz,4H),3.28(t,J＝18.6Hz,2H),3.09–2.95(m,1H),2.71(d,J＝17.3Hz,1H),2.47–2.33(m,1H),2.32–2.16(m,2H),2.15–1.98(m,3H),1.93(d,J＝13.2Hz,2H),1.74(td,J＝13.6,4.2Hz,2H).LCMS(ESI)C 36 H 40 ClN 8 O 4 + [M+H] + Calculated 683.28, measured 683.30.
Example 224: preparation of 4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04065)
Referring to scheme 11, step 2 and the procedure of example 1, 4- (((5 ' -chloro-2 ' - (piperidin-4-ylamino) - [2,4' -bipyridine) prepared in intermediate example 38 was used ]-6-yl) amino) methyl-tetrahydro-2H-pyran-4-carbonitrile (GT-M-159) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS No.: 1312023-72-5) the title compound (GT-04065) was prepared (white solid, 59mg, yield 89.71%). 1 H NMR(400MHz,DMSO)δ11.57(s,1H),11.14(s,1H),8.28(d,J＝13.0Hz,1H),8.21–8.11(m,1H),8.09(s,1H),8.00(dd,J＝7.6,3.1Hz,1H),7.71(dd,J＝23.1,15.7Hz,1H),7.32–6.80(m,3H),5.17(dd,J＝12.8,5.4Hz,1H),4.54(s,2H),3.91(dd,J＝31.9,22.2Hz,3H),3.72(d,J＝8.5Hz,2H),3.44(dt,J＝17.5,8.8Hz,4H),3.15(dd,J＝64.2,10.5Hz,2H),2.97–2.82(m,1H),2.65–2.50(m,2H),2.13(t,J＝13.4Hz,2H),2.09–1.91(m,3H),1.85(d,J＝13.1Hz,2H),1.66(td,J＝13.6,4.1Hz,2H).LCMS(ESI)C 36 H 38 ClN 8 O 5 + [M+H] + Calculated 697.26, measured 697.30.
Example 225: preparation of 4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04068)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of intermediate example 37 was used to prepare 4- (((4- (5-chloro-2- (piperidin-4-ylamino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-158) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) to give the title compound (GT-04068) (white solid, 41mg, yield 63.78%). 1 H NMR(400MHz,DMSO)δ11.39(d,J＝75.1Hz,1H),11.02(s,1H),8.40(d,J＝5.9Hz,1H),8.05(d,J＝21.7Hz,1H),7.94(d,J＝8.9Hz,1H),7.85–7.78(m,2H),7.66(d,J＝22.4Hz,1H),7.56(s,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.53–4.38(m,4H),3.93(dd,J＝11.6,3.1Hz,3H),3.72(dd,J＝16.3,5.6Hz,2H),3.47(dd,J＝12.0,10.5Hz,4H),3.07(dd,J＝22.0,10.4Hz,2H),3.00–2.86(m,1H),2.64(t,J＝16.8Hz,1H),2.47–2.34(m,1H),2.14(t,J＝15.5Hz,2H),2.10–1.96(m,3H),1.90(dd,J＝15.0,7.3Hz,2H),1.79–1.64(m,2H).LCMS(ESI)C 34 H 38 ClN 8 O 4 S + [M+H] + Calculated 689.23, measured 689.30.
Example 226: preparation of 4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04069)
Referring to the procedure of scheme 11, the title compound (GT-04069) (white solid, 40mg, yield 60.63%) was prepared using 4- (((4- (5-chloro-2- (piperidin-4-ylamino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-158) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) obtained in intermediate example 37. 1 H NMR(400MHz,DMSO)δ11.37(d,J＝87.8Hz,1H),11.04(s,1H),8.41(s,1H),8.13–7.94(m,2H),7.73–7.46(m,3H),5.15(dt,J＝16.1,8.1Hz,1H),4.74–4.53(m,2H),4.49(s,2H),4.03(s,1H),3.93(d,J＝9.5Hz,2H),3.71(t,J＝9.0Hz,2H),3.49(dd,J＝24.8,12.6Hz,4H),3.15(s,2H),2.98–2.85(m,1H),2.64(t,J＝16.5Hz,1H),2.42(dd,J＝28.9,19.7Hz,1H),2.17(d,J＝12.1Hz,2H),2.09–1.93(m,3H),1.88(d,J＝13.1Hz,2H),1.77–1.61(m,2H).LCMS(ESI)C 34 H 37 FClN 8 O 4 S + [M+H] + Calculated 707.23, found 707.30.
Example 227: preparation of 4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04070)
The title compound (GT-04070) (white solid, 40mg, yield 60.63%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.39(d,J＝81.7Hz,1H),11.02(d,J＝8.9Hz,1H),8.41(s,1H),8.08(dd,J＝22.6,12.0Hz,2H),7.74–7.46(m,3H),5.14(dt,J＝15.4,7.7Hz,1H),4.50–4.36(m,4H),4.03(s,1H),3.95–3.89(m,2H),3.71(t,J＝8.9Hz,2H),3.49(dd,J＝22.3,11.5Hz,4H),3.15(d,J＝9.1Hz,2H),2.99–2.87(m,1H),2.61(d,J＝16.9Hz,1H),2.41(ddd,J＝26.0,17.5,6.6Hz,1H),2.17(d,J＝11.8Hz,2H),2.07–1.94(m,3H),1.92–1.83(m,2H),1.78–1.65(m,2H).LCMS(ESI)C 34 H 37 FClN 8 O 4 S + [M+H] + Calculated 707.23, found 707.30.
Example 228: preparation of 4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04071)
Referring to the procedure of scheme 11, the title compound (GT-04071) (white solid, 40mg, yield 60.63%) was prepared using 4- (((4- (5-chloro-2- (piperidin-4-ylamino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-158) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) obtained as intermediate example 37. 1 H NMR(400MHz,DMSO)δ11.54(d,J＝66.7Hz,1H),11.03(s,1H),8.41(d,J＝5.6Hz,1H),8.05(d,J＝23.1Hz,1H),7.88–7.48(m,4H),5.11(dd,J＝13.2,5.0Hz,1H),4.58–4.42(m,4H),4.06(s,1H),3.94–3.88(m,2H),3.72(dd,J＝15.3,5.7Hz,2H),3.47(t,J＝11.3Hz,4H),3.28–3.01(m,2H),2.98–2.84(m,1H),2.61(d,J＝16.8Hz,1H),2.46–2.32(m,1H),2.17(d,J＝11.5Hz,2H),2.10–1.95(m,3H),1.93–1.82(m,2H),1.80–1.63(m,2H).LCMS(ESI)C 34 H 37 FClN 8 O 4 S + [M+H] + Calculated 707.23, found 707.30.
Example 229: preparation of 4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04072)
The title compound (GT-04072) (white solid, 41mg, yield 63.78%) was obtained by the method of step 2 and example 1, reference scheme 11. 1 H NMR(400MHz,DMSO)δ11.37(d,J＝56.1Hz,1H),11.11–10.99(m,1H),8.41(d,J＝5.7Hz,1H),8.09–7.92(m,2H),7.81(dd,J＝16.8,7.4Hz,1H),7.74–7.44(m,3H),5.24–5.12(m,1H),4.99(t,J＝16.7Hz,1H),4.54(d,J＝17.6Hz,1H),4.45–4.39(m,2H),4.05(s,1H),3.92(dd,J＝11.6,3.0Hz,2H),3.72(dd,J＝17.0,5.5Hz,2H),3.56–3.37(m,4H),3.20(s,2H),3.02–2.87(m,1H),2.65(d,J＝17.4Hz,1H),2.36(ddd,J＝26.8,13.5,4.4Hz,1H),2.25–1.95(m,5H),1.92–1.82(m,2H),1.82–1.64(m,2H).LCMS(ESI)C 34 H 38 ClN 8 O 4 S + [M+H] + Calculated 689.23, measured 689.30.
Example 230: preparation of 4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-04073)
Referring to scheme 11, step 2 and the procedure of example 1, the procedure of intermediate example 37 was used to prepare 4- (((4- (5-chloro-2- (piperidin-4-ylamino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile (GT-M-158) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5) to give the title compound (GT-04073) (white solid, 40mg, 60.98%). 1 H NMR(400MHz,DMSO)δ11.56(d,J＝67.5Hz,1H),11.16(s,1H),8.40(d,J＝5.7Hz,1H),8.30(d,J＝15.2Hz,1H),8.18(t,J＝9.3Hz,1H),8.10–7.98(m,2H),7.66(dd,J＝56.7,32.7Hz,2H),5.19(dd,J＝12.8,5.4Hz,1H),4.56(s,2H),4.05(s,1H),3.93(dd,J＝11.6,2.9Hz,2H),3.71(t,J＝7.9Hz,2H),3.47(t,J＝11.3Hz,4H),3.14(t,J＝34.4Hz,2H),2.97–2.82(m,1H),2.60(ddd,J＝21.7,17.4,9.8Hz,2H),2.17(d,J＝11.6Hz,2H),2.10–1.94(m,3H),1.93–1.82(m,2H),1.80–1.65(m,2H).LCMS(ESI)C 34 H 36 ClN 8 O 5 S + [M+H] + Calculated 703.21, measured 703.30.
Example 231: preparation of 4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-03377)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-03377) (white solid, 38mg, yield 48.03%) was prepared using 4- (aminomethyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (CAS number 791609-83-1) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.34(s,1H),10.11–9.95(m,2H),9.45(d,J＝1.5Hz,1H),9.18(s,1H),8.94(d,J＝8.3Hz,1H),8.91–8.88(m,1H),8.60(d,J＝5.2Hz,1H),8.15(d,J＝1.3Hz,1H),8.04(d,J＝8.3Hz,2H),7.92(dd,J＝8.0,5.3Hz,1H),7.84–7.78(m,2H),7.73(d,J＝8.4Hz,3H),7.56(d,J＝5.2Hz,1H),7.49(dd,J＝8.2,1.9Hz,1H),7.23(d,J＝8.5Hz,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.47(s,1H),4.38(s,1H),4.30(d,J＝5.1Hz,2H),4.26–4.23(m,2H),2.96–2.86(m,1H),2.64–2.56(m,1H),2.42(dd,J＝13.2,4.6Hz,1H),2.23(s,3H),2.05–1.98(m,1H).LCMS(ESI)C 38 H 35 N 8 O 4 + [M+H] + Calculated 667.27, measured 667.30.
Example 232: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04020)
The title compound (GT-04020) (white solid, 26mg, yield 40.09%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.14–10.76(m,2H),10.56(s,1H),8.81(d,J＝2.3Hz,1H),8.41(d,J＝2.4Hz,1H),8.03–7.89(m,3H),7.84(d,J＝2.1Hz,1H),7.69(d,J＝7.7Hz,1H),7.35(d,J＝9.0Hz,2H),6.75(d,J＝1.7Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.67–4.56(m,3H),4.45(dd,J＝17.6,7.0Hz,2H),3.81(t,J＝10.2Hz,2H),3.49(dd,J＝12.3,7.2Hz,1H),2.96–2.78(m,3H),2.70–2.57(m,4H),2.49–2.37(m,1H),2.22(d,J＝10.3Hz,1H),2.12(d,J＝10.1Hz,1H),2.01(dd,J＝9.8,5.2Hz,1H),1.90(d,J＝11.6Hz,1H).LCMS(ESI)C 36 H 35 ClF 3 N 8 O 5 + [M+H] + Calculated 751.23, measured 751.30.
Example 233: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04021)
The title compound (GT-04021) (white solid, 25mg, yield 38.55%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.03(s,1H),10.92(s,1H),10.56(s,1H),8.81(d,J＝2.4Hz,1H),8.41(d,J＝2.4Hz,1H),8.05(d,J＝4.8Hz,1H),7.95–7.89(m,2H),7.84(d,J＝2.1Hz,1H),7.68(d,J＝8.6Hz,1H),7.35(d,J＝9.1Hz,2H),6.75(d,J＝2.1Hz,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.64(d,J＝12.8Hz,1H),4.50(d,J＝5.6Hz,1H),4.41–4.32(m,2H),3.81(s,2H),3.48(d,J＝13.5Hz,1H),2.96–2.78(m,3H),2.70–2.58(m,4H),2.47–2.34(m,1H),2.22(d,J＝10.3Hz,1H),2.12(d,J＝10.6Hz,1H),2.08–1.99(m,1H),1.90(dd,J＝22.5,10.5Hz,2H).LCMS(ESI)C 36 H 35 ClF 3 N 8 O 5 + [M+H] + Calculated 751.23, measured 751.30.
Example 234: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04022)
The title compound (GT-04022) (white solid, 31mg, yield 47.80%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(500MHz,DMSO)δ11.04(s,1H),10.86(s,1H),10.50(s,1H),8.78(dd,J＝9.9,2.4Hz,1H),8.39(d,J＝2.2Hz,1H),7.91(d,J＝9.1Hz,2H),7.83(d,J＝1.8Hz,1H),7.76–7.61(m,2H),7.36(d,J＝8.9Hz,2H),6.73(d,J＝1.5Hz,1H),5.15–5.04(m,1H),4.44(dddd,J＝36.0,25.5,14.5,5.8Hz,5H),3.80(d,J＝9.6Hz,2H),2.97–2.88(m,1H),2.80(q,J＝11.9Hz,2H),2.61(d,J＝12.8Hz,4H),2.41(ddd,J＝26.7,13.4,4.6Hz,1H),2.15(dd,J＝22.8,11.1Hz,2H),2.05–1.96(m,1H),1.93–1.79(m,2H).LCMS(ESI)C 36 H 35 ClF 3 N 8 O 5 + [M+H] + Calculated 751.23, measured 751.30.
Example 235: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04023)
The title compound (GT-04023) (white solid, 27mg, yield 42.66%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.05(s,1H),10.89(t,J＝34.1Hz,1H),10.54(s,1H),8.81(d,J＝2.4Hz,1H),8.41(d,J＝2.4Hz,1H),7.97–7.89(m,3H),7.86–7.78(m,2H),7.64(dt,J＝7.6,3.8Hz,1H),7.35(d,J＝9.1Hz,2H),6.81–6.69(m,1H),5.22–5.15(m,1H),4.60(d,J＝4.0Hz,1H),4.49(d,J＝17.3Hz,1H),4.22–4.17(m,2H),3.82(d,J＝10.7Hz,2H),3.59–3.53(m,1H),2.94(dd,J＝21.5,9.2Hz,1H),2.83(t,J＝13.0Hz,2H),2.64(dd,J＝10.7,4.7Hz,4H),2.40–2.33(m,1H),2.25–2.12(m,2H),2.03–1.88(m,3H).LCMS(ESI)C 36 H 36 ClF 2 N 8 O 5 + [M+H] + Calculated 733.24, measured 733.30.
Example 236: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04025)
The title compound (GT-04025) (white solid, 34mg, yield 52.70%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(500MHz,DMSO)δ11.15(d,J＝18.1Hz,2H),10.73(s,1H),10.49(s,1H),8.84–8.76(m,1H),8.38(dd,J＝9.2,2.4Hz,1H),8.04(d,J＝7.7Hz,1H),7.95–7.87(m,2H),7.83(dd,J＝9.4,4.6Hz,2H),7.77(s,1H),7.70(d,J＝7.6Hz,1H),7.36(d,J＝8.9Hz,2H),6.70(dd,J＝40.2,2.1Hz,1H),5.14(dd,J＝12.8,5.4Hz,1H),4.68(d,J＝10.1Hz,1H),4.42(dd,J＝12.8,7.4Hz,1H),3.81(d,J＝10.5Hz,2H),2.95–2.85(m,2H),2.80(dd,J＝19.5,11.9Hz,2H),2.66–2.58(m,5H),2.23–1.96(m,4H),1.94–1.85(m,1H).LCMS(ESI)C 36 H 34 ClF 2 N 8 O 6 + [M+H] + Calculated 747.22, measured 747.30.
Example 237: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04052)
Referring to scheme 11, procedure 2 and example 1, N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (CAS number 2699130-63-5) and 3- (5- (bromomethyl) -1-oxoisoindoline were usedThe title compound (GT-04052) (white solid, 37mg, yield 52.30%) was prepared by preparing-2-yl-piperidine-2, 6-dione (GT-03234). 1 H NMR(400MHz,DMSO)δ11.56(s,1H),11.29(s,1H),11.01(s,1H),10.60(s,1H),8.83(d,J＝2.3Hz,1H),8.46(d,J＝2.3Hz,1H),7.95–7.90(m,2H),7.87(s,1H),7.82(dd,J＝7.7,5.8Hz,2H),7.76(d,J＝8.0Hz,1H),7.35(d,J＝8.9Hz,2H),6.82(d,J＝2.1Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.53–4.35(m,5H),3.70(d,J＝12.4Hz,2H),3.53–3.45(m,4H),3.36(t,J＝12.3Hz,2H),3.19–3.11(m,2H),3.04–2.88(m,3H),2.66–2.58(m,1H),2.43(dd,J＝13.1,4.5Hz,1H),2.36(dd,J＝12.0,6.8Hz,2H),2.24–2.13(m,2H),2.04–1.98(m,1H).LCMS(ESI)C 39 H 41 ClF 2 N 9 O 5 + [M+H] + Calculated 788.28, measured 788.30.
Example 238: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04053)
Referring to the procedure of scheme 11, the title compound (GT-04053) (white solid, 43mg, yield 59.42%) was prepared using N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (CAS number 2699130-63-5) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445). 1 H NMR(400MHz,DMSO)δ11.63(s,1H),11.03(s,1H),10.59(s,1H),8.83(d,J＝2.3Hz,1H),8.46(d,J＝2.3Hz,1H),7.93(dd,J＝7.4,5.3Hz,3H),7.82(d,J＝2.0Hz,1H),7.69(d,J＝7.7Hz,1H),7.35(d,J＝8.9Hz,2H),6.82(d,J＝2.1Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.69–4.37(m,5H),3.69(s,2H),3.61(s,3H),3.47(d,J＝10.5Hz,2H),3.35(d,J＝12.4Hz,2H),3.16–3.07(m,3H),2.96–2.89(m,1H),2.61(d,J＝17.0Hz,1H),2.47–2.31(m,3H),2.19(d,J＝11.4Hz,2H),2.04–1.97(m,1H).LCMS(ESI)C 39 H 40 ClF 3 N 9 O 5 + [M+H] + Calculated 806.27, measured 806.30.
Example 239: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04054)
The title compound (GT-04054) (white solid, 40mg, yield 55.27%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.60(s,1H),11.02(s,1H),10.59(s,1H),8.83(d,J＝2.2Hz,1H),8.46(d,J＝2.3Hz,1H),8.02(d,J＝6.0Hz,1H),7.97–7.85(m,2H),7.82(d,J＝1.9Hz,1H),7.67(d,J＝8.5Hz,1H),7.35(d,J＝8.9Hz,2H),6.82(d,J＝2.1Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.67–4.32(m,5H),3.72(s,2H),3.59(d,J＝10.6Hz,2H),3.46(d,J＝9.1Hz,3H),3.40–3.33(m,2H),3.17–3.08(m,3H),2.95–2.87(m,1H),2.65–2.58(m,1H),2.44(dd,J＝13.2,4.6Hz,1H),2.35(d,J＝9.1Hz,2H),2.19(dd,J＝23.5,12.1Hz,2H),2.05–1.98(m,1H).LCMS(ESI)C 39 H 40 ClF 3 N 9 O 5 + [M+H] + Calculated 806.27, measured 806.30.
Example 240: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04055)
Referring to the procedure of scheme 11, the title compound (GT-04055) (white solid, 44mg, yield 60.80%) was prepared using N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (CAS number 2699130-63-5) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446). 1 H NMR(400MHz,DMSO)δ11.54(s,1H),11.06(s,1H),10.59(s,1H),8.83(d,J＝2.3Hz,1H),8.46(d,J＝2.3Hz,1H),7.98(d,J＝7.6Hz,1H),7.92(d,J＝9.1Hz,2H),7.83(d,J＝7.8Hz,2H),7.64(t,J＝7.6Hz,1H),7.35(d,J＝8.8Hz,2H),6.82(d,J＝2.1Hz,1H),5.21–5.16(m,1H),4.84(d,J＝17.6Hz,1H),4.46(dd,J＝41.0,14.2Hz,4H),3.71(d,J＝12.8Hz,2H),3.57–3.45(m,5H),3.36(t,J＝12.3Hz,2H),3.16(d,J＝7.0Hz,3H),2.99–2.90(m,1H),2.65(d,J＝16.9Hz,1H),2.43–2.31(m,3H),2.30–2.17(m,2H),2.08–2.02(m,1H).LCMS(ESI)C 39 H 40 ClF 3 N 9 O 5 + [M+H] + Calculated 806.27, measured 806.30.
Example 241: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04056)
The title compound (GT-04056) (white solid, 44mg, yield 62.20%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.48(s,1H),11.02(s,1H),10.59(s,1H),8.83(d,J＝2.2Hz,1H),8.46(d,J＝2.2Hz,1H),7.92(d,J＝9.1Hz,2H),7.83(d,J＝2.0Hz,1H),7.66(d,J＝12.7Hz,2H),7.35(d,J＝8.9Hz,2H),6.82(d,J＝2.0Hz,1H),5.10(dd,J＝13.2,5.0Hz,1H),4.58–4.35(m,5H),3.70(s,2H),3.50(d,J＝15.1Hz,4H),3.40–3.31(m,2H),3.20–3.12(m,2H),3.04–2.85(m,3H),2.61(d,J＝16.8Hz,1H),2.45–2.30(m,3H),2.20(dd,J＝23.2,11.6Hz,2H),2.05–1.93(m,1H).LCMS(ESI)C 39 H 41 ClF 2 N 9 O 5 + [M+H] + Calculated 788.28, measured 788.30.
Example 242: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04057)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-04057) was prepared using N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (CAS number 2699130-63-5) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5) (white solid, 44mg, yield 61.11%). 1 H NMR(400MHz,DMSO)δ11.54(s,1H),11.15(s,1H),10.59(s,1H),8.83(d,J＝2.2Hz,1H),8.46(d,J＝2.2Hz,1H),8.24(s,1H),8.13(d,J＝7.8Hz,1H),8.03(d,J＝7.6Hz,1H),7.92(d,J＝9.1Hz,2H),7.82(d,J＝1.9Hz,1H),7.35(d,J＝8.9Hz,2H),6.82(d,J＝2.0Hz,1H),5.19(dd,J＝12.8,5.4Hz,1H),4.54(s,2H),3.72(s,2H),3.55–3.46(m,5H),3.39–3.31(m,2H),3.15(d,J＝8.2Hz,2H),3.09–2.98(m,2H),2.95–2.86(m,1H),2.66–2.53(m,2H),2.35(d,J＝11.2Hz,2H),2.28–2.14(m,2H),2.08(dd,J＝9.0,3.6Hz,1H).LCMS(ESI)C 39 H 39 ClF 2 N 9 O 6 + [M+H] + Calculated 802.26, measured 802.30.
Example 243: preparation of N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04100)
Referring to scheme 11, step 2 and the procedure of example 1,3- (imidazo [1,2-b ] prepared in intermediate example 70 is used ]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-111) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-04100) (white solid, 27mg, yield 38.18%). LCMS (ESI) C 43 H 40 F 3 N 8 O 4 + [M+H] + Calculated 789.30, measured 789.30.
Example 244: preparation of N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04101)
Referring to the procedure of scheme 11, 3- (imidazo [1,2-b ] prepared in intermediate example 70]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-111) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) were prepared to give the title compound (GT-04101) (white solid, 55mg, yield 76.03%). 1 H NMR(400MHz,DMSO)δ11.03(s,1H),10.60(s,1H),8.77(dd,J＝4.4,1.4Hz,1H),8.33–8.26(m,2H),8.21(dd,J＝11.0,2.0Hz,2H),8.10(d,J＝6.1Hz,2H),7.98(dd,J＝8.0,1.7Hz,1H),7.70(d,J＝8.4Hz,1H),7.57(dd,J＝13.8,7.3Hz,2H),7.45(dd,J＝9.2,4.5Hz,1H),5.16(dd,J＝13.8,4.9Hz,1H),4.67(d,J＝15.1Hz,1H),4.57–4.37(m,3H),3.42(s,1H),3.07(s,2H),2.92–2.85(m,2H),2.70(d,J＝18.0Hz,3H),2.62(d,J＝9.1Hz,4H),2.39(ddd,J＝22.4,12.8,7.1Hz,2H),2.23(d,J＝9.9Hz,1H),2.03(dd,J＝11.3,6.0Hz,2H),1.92(d,J＝11.5Hz,2H).LCMS(ESI)C 43 H 39 F 4 N 8 O 4 + [M+H] + Calculated 807.30, measured 807.30.
Example 245: preparation of N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04102)
The title compound (GT-04102) (white solid, 40mg, yield 55.30%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(500MHz,DMSO)δ11.05(d,J＝7.4Hz,1H),10.73(s,1H),10.60(s,1H),8.76(d,J＝4.3Hz,1H),8.30(dd,J＝9.3,1.4Hz,2H),8.21(dd,J＝14.2,2.1Hz,2H),8.09(dd,J＝20.3,6.4Hz,2H),7.98(dd,J＝8.0,1.6Hz,1H),7.70(t,J＝12.7Hz,1H),7.58(dd,J＝19.4,8.6Hz,2H),7.44(ddd,J＝9.2,4.5,0.9Hz,1H),5.21–5.10(m,1H),4.69(d,J＝13.0Hz,1H),4.51(dt,J＝20.1,10.2Hz,1H),4.45–4.32(m,2H),3.43(s,1H),3.07(s,2H),3.00–2.80(m,3H),2.73(t,J＝4.5Hz,3H),2.63(d,J＝11.7Hz,4H),2.47–2.38(m,1H),2.35(dd,J＝16.1,6.4Hz,1H),2.23(d,J＝10.4Hz,1H),2.09–2.00(m,1H),1.97–1.82(m,2H).LCMS(ESI)C 43 H 39 F 4 N 8 O 4 + [M+H] + Calculated 807.30, measured 807.30.
Example 246: preparation of N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04103)
Referring to the procedure of scheme 11, 3- (imidazo [1,2-b ] prepared in intermediate example 70]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-111) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) were prepared to give the title compound (GT-04103) (white solid, 46mg, yield 63.59%). 1 H NMR(400MHz,DMSO)δ11.24(s,1H),11.03(s,1H),10.59(s,1H),8.76(dd,J＝4.4,1.4Hz,1H),8.34–8.26(m,2H),8.21(dd,J＝12.3,2.0Hz,2H),8.08(t,J＝10.7Hz,1H),7.98(dd,J＝8.0,1.7Hz,1H),7.77(d,J＝11.2Hz,2H),7.62–7.50(m,2H),7.44(dt,J＝10.7,5.3Hz,1H),5.11(dt,J＝13.0,6.5Hz,1H),4.70–4.49(m,2H),4.41(dt,J＝18.2,9.3Hz,2H),3.36(s,1H),3.05(d,J＝8.0Hz,2H),2.98–2.77(m,3H),2.70–2.57(m,7H),2.47–2.36(m,1H),2.36–2.22(m,2H),2.09–1.99(m,1H),1.97–1.77(m,2H).LCMS(ESI)C 43 H 39 F 4 N 8 O 4 + [M+H] + Calculated 807.30, measured 807.30.
Example 247: preparation of N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04104)
The title compound (GT-04104) (white solid, 45mg, 63.63% yield) was prepared according to the procedure for step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ10.98(d,J＝10.0Hz,1H),10.83(d,J＝50.8Hz,1H),10.53(s,1H),8.69(dd,J＝4.4,1.4Hz,1H),8.23(dd,J＝8.9,1.8Hz,2H),8.15(dd,J＝10.3,2.0Hz,2H),8.04(d,J＝8.5Hz,1H),7.99–7.86(m,2H),7.79(t,J＝7.6Hz,1H),7.64–7.57(m,1H),7.51(dd,J＝18.3,8.6Hz,2H),7.37(dd,J＝9.2,4.5Hz,1H),5.18–5.06(m,1H),5.00–4.65(m,1H),4.63–4.41(m,2H),4.17(dt,J＝18.5,8.9Hz,1H),3.43(d,J＝10.6Hz,1H),3.03(d,J＝8.1Hz,2H),2.94–2.77(m,3H),2.66–2.52(m,7H),2.37–2.18(m,3H),2.04–1.78(m,3H).LCMS(ESI)C 43 H 40 F 3 N 8 O 4 + [M+H] + Calculated 789.30, measured 789.30.
Example 248: preparation of N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04105)
Referring to scheme 11, step 2 and the procedure of example 1,3- (imidazo [1, 2-b) is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (methylamino) piperidin-1-yl) -3- (trifluoromethyl) benzeneBase) benzamide (GT-D-111) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) the title compound (GT-04105) was prepared (white solid, 57mg, yield 79.19%). 1 H NMR(500MHz,DMSO)δ10.85(s,1H),10.58(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.32–8.29(m,1H),8.29–8.27(m,1H),8.22(d,J＝1.7Hz,1H),8.19(d,J＝2.3Hz,1H),8.09(dd,J＝9.7,7.5Hz,1H),8.06(d,J＝7.7Hz,1H),8.03–8.00(m,1H),7.99–7.93(m,3H),7.64–7.52(m,2H),7.43(dd,J＝9.2,4.4Hz,1H),5.20–5.17(m,1H),4.97(s,2H),3.41(s,1H),3.07(s,1H),2.89(ddd,J＝11.7,6.2,2.9Hz,2H),2.67–2.58(m,8H),2.27(s,2H),2.07(ddd,J＝10.7,5.4,2.8Hz,3H),1.90(dd,J＝19.3,11.4Hz,2H).LCMS(ESI)C 43 H 38 F 3 N 8 O 5 + [M+H] + Calculated 803.28, measured 803.30.
Example 249: preparation of 3- (4-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03900)
The procedure described in scheme 11 was followed using 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]]Imidazol-6-yl) -N- (5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1873300-67-4) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03900) (white solid, 50.00mg, yield 71.07%). 1 H NMR(400MHz,DMSO)δ11.67(s,1H),11.02(s,1H),8.84(d,J＝3.4Hz,1H),8.28(s,1H),8.21–8.14(m,1H),7.95(s,1H),7.89–7.74(m,3H),7.67(d,J＝7.7Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.89(dd,J＝13.8,6.9Hz,1H),4.59(d,J＝17.6Hz,1H),4.46(s,1H),4.38–4.33(m,1H),3.87(d,J＝11.4Hz,2H),3.71–3.65(m,3H),3.54–3.42(m,6H),2.96–2.89(m,1H),2.81(t,J＝11.6Hz,2H),2.72(s,3H),2.61(dd,J＝16.9,1.0Hz,2H),2.43(dd,J＝9.4,4.2Hz,1H),2.23(dd,J＝8.1,5.0Hz,2H),2.05–1.98(m,1H),1.92–1.82(m,2H),1.64(d,J＝6.9Hz,6H).LCMS(ESI)C 43 H 47 F 3 N 11 O 3 + [M+H] + Calculated value822.37, found 822.40.
Example 250: preparation of 3- (6-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03901)
The title compound (GT-03901) (white solid, 50.00mg, yield 71.07%) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.75(s,1H),11.01(s,1H),8.86(d,J＝3.0Hz,1H),8.30(s,1H),8.21(d,J＝9.9Hz,1H),8.04–7.91(m,2H),7.80(t,J＝9.5Hz,2H),7.65(d,J＝8.4Hz,1H),5.14(dd,J＝13.2,4.7Hz,1H),4.96–4.88(m,1H),4.42(d,J＝32.6Hz,3H),3.89(s,2H),3.69(d,J＝6.6Hz,3H),3.57–3.45(m,6H),2.96–2.88(m,1H),2.82(t,J＝12.5Hz,2H),2.74(s,3H),2.61(dd,J＝17.4,2.8Hz,1H),2.47–2.32(m,2H),2.23(d,J＝11.1Hz,2H),2.06–1.99(m,1H),1.91–1.79(m,2H),1.64(d,J＝6.8Hz,6H).LCMS(ESI)C 43 H 47 F 3 N 11 O 3 + [M+H] + Calculated 822.37, measured 822.40.
Example 251: preparation of 3- (7-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03902)
The procedure described in scheme 11 was followed using 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]]Imidazol-6-yl) -N- (5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1873300-67-4) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-03902) (white solid, 50.00mg, yield 71.07%). 1 H NMR(400MHz,DMSO)δ11.70(s,1H),11.01(s,1H),8.85(d,J＝3.4Hz,1H),8.29(s,1H),8.19(d,J＝8.1Hz,1H),7.95(s,1H),7.83–7.67(m,4H),5.10(dd,J＝13.2,5.1Hz,1H),4.91(dt,J＝13.8,6.8Hz,1H),4.51–4.41(m,3H),3.89(s,2H),3.68(s,3H),3.57–3.45(m,6H),2.93–2.79(m,3H),2.73(s,3H),2.60(dd,J＝16.2,2.2Hz,2H),2.44–2.38(m,1H),2.24(d,J＝10.9Hz,2H),2.04–1.98(m,1H),1.87(ddd,J＝20.3,12.6,7.4Hz,2H),1.64(d,J＝6.9Hz,6H).LCMS(ESI)C 43 H 47 F 3 N 11 O 3 + [M+H] + Calculated 822.37, measured 822.40.
Example 252: preparation of 3- (4- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03903)
The title compound (GT-03903) (white solid, 50.00mg, yield 72.66%) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.04(s,1H),8.84(d,J＝3.3Hz,1H),8.28(s,1H),8.18(dd,J＝9.9,1.7Hz,1H),7.95(d,J＝1.6Hz,2H),7.78(dd,J＝15.0,10.5Hz,3H),7.61(t,J＝7.5Hz,1H),5.17(dd,J＝13.0,5.2Hz,1H),4.90(dt,J＝14.0,6.8Hz,2H),4.51(d,J＝17.6Hz,2H),3.88(s,2H),3.70–3.66(m,3H),3.53–3.38(m,6H),2.94(dd,J＝10.8,6.2Hz,1H),2.80(d,J＝12.0Hz,2H),2.72(s,3H),2.67–2.58(m,2H),2.40–2.34(m,1H),2.26–2.17(m,2H),2.06–2.01(m,1H),1.87(dt,J＝12.1,8.7Hz,2H),1.64(d,J＝6.9Hz,6H).LCMS(ESI)C 43 H 48 F 2 N 11 O 3 + [M+H] + Calculated 804.38, measured 804.40.
Example 253: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-03904)
Referring to scheme 11, step 2 and the method of example 1, 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] is used]Imidazol-6-yl) -N- (5- (4- (piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1873300-67-4) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS No.: 1312023-72-5) to give the objective compound (GT-03904) (white solid, 50.00mg, yield 71.42%). 1 H NMR(400MHz,DMSO)δ11.68(s,1H),11.14(s,1H),8.84(d,J＝3.4Hz,1H),8.27(d,J＝8.9Hz,2H),8.20–8.12(m,2H),8.01(d,J＝7.6Hz,1H),7.95(d,J＝1.8Hz,1H),7.79(dd,J＝20.3,10.7Hz,2H),5.18(dd,J＝12.9,5.3Hz,1H),4.91(dd,J＝13.9,7.0Hz,1H),4.51(tdd,J＝23.8,15.9,8.0Hz,3H),3.87(d,J＝11.7Hz,2H),3.72–3.66(m,3H),3.56(ddd,J＝13.5,8.6,4.1Hz,5H),2.90–2.79(m,3H),2.72(s,3H),2.60(dd,J＝21.8,6.6Hz,2H),2.23(d,J＝10.1Hz,2H),2.11–2.04(m,1H),1.92–1.83(m,2H),1.64(d,J＝6.9Hz,6H).LCMS(ESI)C 43 H 46 F 2 N 11 O 4 + [M+H] + Calculated 818.36, measured 818.40.
Example 254: preparation of 2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) acetamide (GT-03378)
The method of scheme 56 is followed using (S) -2- (4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3, 2-f) ][1,2,4]Triazolo [4,3-a ]][1,4]Diazepan-6-yl) acetic acid (CAS number: 202592-23-2) and 3- (5- (aminomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (CAS number: 1010100-28-3) the title compound (GT-03378) was prepared (white solid, 49mg, yield 58.68%). 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.90(t,J＝5.6Hz,1H),7.67(dd,J＝7.8,3.0Hz,1H),7.56(s,1H),7.46(d,J＝8.6Hz,3H),7.40–7.34(m,2H),5.12(dd,J＝13.1,5.0Hz,1H),4.58(td,J＝7.1,2.6Hz,1H),4.46(d,J＝6.1Hz,2H),4.43–4.36(m,1H),4.34–4.26(m,1H),3.35(d,J＝7.3Hz,2H),2.92(ddd,J＝17.7,13.7,5.4Hz,1H),2.62(s,3H),2.62–2.54(m,1H),2.41(s,3H),2.39–2.30(m,1H),2.03–1.94(m,1H),1.61(d,J＝3.3Hz,3H).LCMS(ESI)C 33 H 31 ClN 7 O 4 S + [M+H] + Calculated 656.18, measured 656.20.
Example 255: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03728)
Referring to the procedure of scheme 11, 2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyridine prepared in intermediate example 29 was used-4-yl) amino) -N-methylbenzamide (GT-M-172) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03728) (white solid, 51mg, yield 71.79%). 1 H NMR(400MHz,DMSO)δ11.44(d,J＝15.0Hz,1H),11.04(s,1H),10.62(s,1H),10.05(s,1H),8.86(d,J＝4.6Hz,1H),8.18(s,1H),8.03(t,J＝6.3Hz,1H),7.78(d,J＝7.8Hz,1H),7.69(d,J＝7.7Hz,1H),7.56(d,J＝4.0Hz,2H),7.27(dt,J＝13.8,5.1Hz,2H),6.86(s,1H),6.73(s,1H),6.57(s,1H),5.18–5.14(m,1H),4.66–4.57(m,2H),4.43(dd,J＝19.6,10.6Hz,2H),3.93(d,J＝11.8Hz,2H),3.82(s,3H),3.60–3.54(m,2H),2.97–2.88(m,3H),2.75(d,J＝4.5Hz,3H),2.68(d,J＝1.8Hz,3H),2.61(d,J＝16.1Hz,1H),2.43–2.37(m,1H),2.25(d,J＝13.3Hz,1H),2.03(dd,J＝10.6,5.1Hz,3H).LCMS(ESI)C 41 H 43 F 4 N 8 O 5 + [M+H] + Calculated 803.32, measured 803.30.
Example 256: preparation of 3- (5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03792)
Referring to scheme 11, step 2 and the method of example 1, N prepared in intermediate example 35 was used 4 - (3- (methylsulfonyl) benzyl) -N 2 - (4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (GT-M-191) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-03792) (white solid, 18mg, yield 29.29%). 1 H NMR(400MHz,DMSO)δ11.55(s,1H),11.02(s,1H),8.36(s,1H),7.92(d,J＝16.2Hz,2H),7.81(d,J＝12.3Hz,3H),7.59(dd,J＝19.6,12.0Hz,2H),7.28(d,J＝6.1Hz,2H),6.89(d,J＝8.5Hz,2H),5.15(dd,J＝13.2,4.8Hz,1H),4.71(d,J＝5.0Hz,2H),4.52(t,J＝8.6Hz,3H),4.39(d,J＝17.7Hz,1H),3.39(d,J＝5.2Hz,3H),3.19(dd,J＝22.2,14.5Hz,9H),2.92(t,J＝8.7Hz,1H),2.61(d,J＝16.8Hz,1H),2.43(dd,J＝13.2,4.0Hz,1H),2.04–1.99(m,1H).LCMS(ESI)C 37 H 38 F 3 N 8 O 5 S + [M+H] + Calculated 763.26, measured 763.30.
Example 257: preparation of 3- (4-fluoro-5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03817)
Referring to the procedure of scheme 11, N prepared in intermediate example 35 was used 4 - (3- (methylsulfonyl) benzyl) -N 2 - (4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (GT-M-191) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03817) (white solid, 26.00mg, yield 33.74%). 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.04(s,1H),10.68(s,1H),8.96(s,1H),8.44(s,1H),8.06–8.00(m,1H),7.90(s,1H),7.81(d,J＝7.4Hz,1H),7.70(d,J＝7.7Hz,1H),7.61(t,J＝7.7Hz,1H),7.56–7.40(m,1H),7.27(d,J＝7.9Hz,2H),6.91(d,J＝8.7Hz,2H),5.16(dd,J＝13.2,5.0Hz,1H),4.72(d,J＝5.4Hz,2H),4.65–4.56(m,3H),4.46(d,J＝17.6Hz,1H),3.77(d,J＝7.9Hz,3H),3.51(s,2H),3.30–3.17(m,4H),3.15(s,3H),2.97–2.89(m,1H),2.61(d,J＝16.8Hz,1H),2.49–2.39(m,1H),2.06–1.99(m,1H).LCMS(ESI)C 37 H 37 F 4 N 8 O 5 S + [M+H] + Calculated 781.25, measured 781.30.
Example 258: preparation of 3- (6-fluoro-5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03818)
The title compound (GT-03818) (white solid, 19.00mg, yield 24.65%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.44(s,1H),11.03(s,1H),10.25(s,1H),8.61(s,1H),8.34(s,1H),8.10(d,J＝6.0Hz,1H),7.90(s,1H),7.80(d,J＝7.2Hz,1H),7.69(d,J＝8.4Hz,1H),7.60(d,J＝7.6Hz,1H),7.57–7.47(m,1H),7.30(d,J＝7.3Hz,2H),6.89(d,J＝8.8Hz,2H),5.15(dd,J＝13.2,5.1Hz,1H),4.71(d,J＝5.4Hz,2H),4.58–4.46(m,4H),4.38(d,J＝17.5Hz,1H),3.49(d,J＝7.9Hz,4H),3.24(d,J＝26.6Hz,4H),3.14(s,3H),2.96–2.89(m,1H),2.64–2.59(m,1H),2.44(dd,J＝13.1,4.6Hz,1H),2.06–2.00(m,1H).LCMS(ESI)C 37 H 37 F 4 N 8 O 5 S + [M+H] + Calculated 781.25, measured 781.30.
Example 259: preparation of 3- (7-fluoro-5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03819)
Referring to the procedure of scheme 11, N prepared in intermediate example 35 was used 4 - (3- (methylsulfonyl) benzyl) -N 2 - (4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (GT-M-191) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (GT-03819) (white solid, 15.00mg, yield 19.46%). 1 H NMR(400MHz,DMSO)δ11.62(s,1H),11.03(s,1H),10.21(s,1H),8.60(s,1H),8.34(s,1H),7.90(s,1H),7.80(d,J＝7.3Hz,1H),7.72(d,J＝11.6Hz,2H),7.61(t,J＝7.6Hz,1H),7.58–7.45(m,1H),7.30(d,J＝7.5Hz,2H),6.88(d,J＝8.4Hz,2H),5.11(dd,J＝13.2,5.0Hz,1H),4.71(d,J＝5.6Hz,2H),4.62–4.30(m,5H),3.41(d,J＝6.8Hz,3H),3.27–3.07(m,8H),2.96–2.87(m,1H),2.67–2.58(m,1H),2.44–2.33(m,1H),2.01(dt,J＝7.8,3.2Hz,1H).LCMS(ESI)C 37 H 37 F 4 N 8 O 5 S + [M+H] + Calculated 781.25, measured 781.30.
Example 260: preparation of 3- (4- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03820)
The title compound (GT-03820) (white solid, 22.00mg, yield 29.22%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.51(s,1H),11.07(s,1H),10.33(s,1H),8.68(s,1H),8.36(s,1H),8.06(d,J＝7.6Hz,1H),7.90(s,1H),7.84(d,J＝7.5Hz,1H),7.80(d,J＝7.4Hz,1H),7.67–7.59(m,2H),7.58–7.49(m,1H),7.29(d,J＝6.3Hz,2H),6.89(d,J＝8.5Hz,2H),5.19(dd,J＝13.1,5.1Hz,1H),4.94(d,J＝17.6Hz,1H),4.72(d,J＝5.3Hz,2H),4.54(d,J＝17.6Hz,1H),4.46(s,2H),3.76(d,J＝10.1Hz,3H),3.47(d,J＝8.8Hz,1H),3.40(d,J＝10.4Hz,1H),3.31–3.20(m,4H),3.15(s,3H),2.99–2.91(m,1H),2.68–2.61(m,1H),2.34(td,J＝13.4,8.9Hz,1H),2.08–2.01(m,1H).LCMS(ESI)C 37 H 38 F 3 N 8 O 5 S + [M+H] + Calculated 763.26, measured 763.30.
Example 261: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-03821)
Referring to scheme 11, step 2 and the method of example 1, N prepared in intermediate example 35 was used 4 - (3- (methylsulfonyl) benzyl) -N 2 - (4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (GT-M-191) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) gave the title compound (GT-03821) (white solid, 25.00mg, yield 32.60%). 1 H NMR(400MHz,DMSO)δ11.73(s,1H),11.16(s,1H),10.32(s,1H),8.67(s,1H),8.33(d,J＝21.0Hz,2H),8.18(d,J＝7.9Hz,1H),8.05(d,J＝7.6Hz,1H),7.90(s,1H),7.80(d,J＝7.3Hz,1H),7.64–7.51(m,2H),7.29(d,J＝8.1Hz,2H),6.89(d,J＝8.6Hz,2H),5.19(dd,J＝12.8,5.3Hz,1H),4.71(d,J＝5.4Hz,2H),4.60(s,2H),3.76(d,J＝7.8Hz,3H),3.40(d,J＝8.1Hz,2H),3.21–3.12(m,7H),2.95–2.86(m,1H),2.66–2.54(m,2H),2.11–2.05(m,1H).LCMS(ESI)C 37 H 36 F 3 N 8 O 6 S + [M+H] + Calculated 777.24, measured 777.30.
Example 262: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03940)
The title compound (GT-03940) (white solid, 30.00mg, yield 49.32%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.70(s,1H),11.01(s,1H),10.56(s,1H),9.66(s,1H),8.78(d,J＝4.6Hz,1H),8.23(s,1H),7.98(s,1H),7.85(q,J＝7.9Hz,2H),7.76(d,J＝6.9Hz,1H),7.60(d,J＝7.8Hz,1H),7.52(t,J＝7.4Hz,1H),7.29–7.19(m,2H),6.70(s,1H),6.60(s,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.60–4.50(m,4H),4.39(d,J＝17.6Hz,1H),3.37(d,J＝8.1Hz,2H),3.21(d,J＝11.4Hz,5H),2.92(dd,J＝10.9,6.8Hz,1H),2.75(d,J＝4.5Hz,3H),2.62(d,J＝16.6Hz,2H),2.44(dd,J＝13.3,4.6Hz,1H),2.18(s,3H),2.06–2.00(m,1H),1.18(s,3H),1.17(s,3H).LCMS(ESI)C 42 H 46 F 3 N 8 O 5 + [M+H] + Calculated 799.35, measured 799.40.
Example 263: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03941)
The title compound (GT-03941) (white solid, 30.00mg, yield 48.23%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.64(s,1H),11.05(s,1H),10.58(s,1H),9.69(s,1H),8.80(q,J＝4.0Hz,1H),8.23(s,1H),8.05(t,J＝6.9Hz,1H),7.76(d,J＝7.4Hz,1H),7.71(d,J＝7.7Hz,1H),7.60(d,J＝7.8Hz,1H),7.52(t,J＝7.6Hz,1H),7.28–7.20(m,2H),6.70(s,1H),6.61(s,1H),5.16(dd,J＝13.2,5.1Hz,1H),4.56(ddd,J＝27.4,21.7,16.6Hz,5H),3.30(dd,J＝10.9,5.2Hz,3H),3.19(s,5H),2.97–2.89(m,1H),2.75(d,J＝4.5Hz,3H),2.61(d,J＝16.1Hz,1H),2.44(dd,J＝11.5,3.5Hz,1H),2.18(s,3H),2.04–1.98(m,1H),1.18(s,3H),1.17(s,3H).LCMS(ESI)C 42 H 45 F 4 N 8 O 5 + [M+H] + Calculated 817.34, measured 817.30.
Example 264: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03942)
The title compound (GT-03942) was obtained (white solid, 30.00mg, yield 48.23%) by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.69(s,1H),11.04(s,1H),10.60(s,1H),9.75(s,1H),8.81(d,J＝4.6Hz,1H),8.24(s,1H),8.16(d,J＝6.0Hz,1H),7.76(d,J＝7.4Hz,1H),7.70(d,J＝8.4Hz,1H),7.60(d,J＝8.1Hz,1H),7.53(t,J＝7.5Hz,1H),7.24(dd,J＝14.6,6.9Hz,2H),6.69(s,1H),6.61(s,1H),5.16(dd,J＝13.2,5.1Hz,1H),4.58–4.35(m,5H),3.36–3.28(m,3H),3.19(d,J＝0.7Hz,5H),2.96–2.88(m,1H),2.75(d,J＝4.5Hz,3H),2.61(dd,J＝14.9,2.0Hz,1H),2.48–2.39(m,1H),2.18(s,3H),2.02(dd,J＝11.1,5.8Hz,1H),1.18(s,3H),1.17(s,3H).LCMS(ESI)C 42 H 45 F 4 N 8 O 5 + [M+H] + Calculated 817.34, measured 817.30.
Example 265: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03943)
The title compound (GT-03943) (white solid, 30.00mg, yield 48.23%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.87(s,1H),11.02(s,1H),10.57(s,1H),9.67(s,1H),8.78(d,J＝4.5Hz,1H),8.23(s,1H),7.77(dd,J＝10.6,6.2Hz,3H),7.60(d,J＝8.0Hz,1H),7.52(t,J＝7.7Hz,1H),7.29–7.18(m,2H),6.71(s,1H),6.60(s,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.59–4.50(m,4H),4.41(d,J＝18.1Hz,1H),3.29–3.13(m,8H),2.96–2.89(m,1H),2.75(d,J＝4.5Hz,3H),2.61(d,J＝16.4Hz,1H),2.40(dd,J＝13.2,8.8Hz,1H),2.18(s,3H),2.02(dd,J＝10.7,5.4Hz,1H),1.19(s,3H),1.17(s,3H).LCMS(ESI)C 42 H 45 F 4 N 8 O 5 + [M+H] + Calculated 817.34, measured 817.30.
Example 266: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03944)
The title compound (GT-03944) (white solid, 30.00mg, yield 49.32%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.60(s,1H),11.07(s,1H),10.57(s,1H),9.69(s,1H),8.77(dd,J＝8.2,3.7Hz,1H),8.23(s,1H),8.12(d,J＝7.6Hz,1H),7.84(d,J＝7.5Hz,1H),7.76(d,J＝7.8Hz,1H),7.65(t,J＝7.6Hz,1H),7.60(d,J＝7.9Hz,1H),7.53(t,J＝7.6Hz,1H),7.25(dd,J＝15.1,7.2Hz,2H),6.70(s,1H),6.60(s,1H),5.19(dd,J＝13.2,5.1Hz,1H),4.96(d,J＝17.6Hz,1H),4.60–4.43(m,4H),3.32–3.13(m,8H),3.00–2.92(m,1H),2.75(d,J＝4.5Hz,3H),2.69–2.62(m,1H),2.40–2.31(m,1H),2.20(s,3H),2.09–2.01(m,1H),1.18(s,3H),1.17(s,3H).LCMS(ESI)C 42 H 46 F 3 N 8 O 5 + [M+H] + Calculated 799.35, measured 799.40.
Example 267: preparation of 2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03945)
The title compound (GT-03945) (white solid, 30.00mg, yield 48.47%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.88(s,1H),11.15(s,1H),10.56(s,1H),9.63(s,1H),8.78(q,J＝4.2Hz,1H),8.34(s,1H),8.22(d,J＝6.4Hz,2H),8.05(d,J＝7.7Hz,1H),7.76(d,J＝7.0Hz,1H),7.59(d,J＝8.1Hz,1H),7.52(t,J＝7.6Hz,1H),7.31–7.17(m,2H),6.70(s,1H),6.60(s,1H),5.19(dd,J＝12.8,5.3Hz,1H),4.68–4.51(m,3H),3.22(d,J＝28.8Hz,7H),2.96–2.87(m,1H),2.75(d,J＝4.5Hz,3H),2.66–2.52(m,3H),2.18(s,3H),2.08(dd,J＝9.0,3.6Hz,1H),1.18(s,3H),1.17(s,3H).LCMS(ESI)C 42 H 44 F 3 N 8 O 6 + [M+H] + Calculated 813.33, measured 813.30.
Example 268: preparation of N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (GT-04028)
The title compound (GT-04028) (white solid, 27mg, yield 36.60%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.89(s,1H),8.63(t,J＝2.7Hz,1H),8.48–8.40(m,1H),8.35(d,J＝9.5Hz,1H),7.87(d,J＝5.4Hz,1H),7.83(d,J＝7.8Hz,1H),7.77(d,J＝7.8Hz,1H),7.65(t,J＝7.8Hz,1H),7.49(d,J＝7.5Hz,1H),7.36(dd,J＝13.6,4.8Hz,1H),7.25(d,J＝7.9Hz,1H),7.13(d,J＝6.4Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.54–4.36(m,8H),3.95(dd,J＝11.1,7.3Hz,1H),3.85(d,J＝7.3Hz,3H),3.13–3.05(m,2H),2.92(d,J＝4.5Hz,3H),2.64–2.59(m,1H),2.45–2.38(m,1H),2.05–1.89(m,6H).LCMS(ESI)C 41 H 39 F 4 N 8 O 7 + [M+H] + Calculated 831.28, measured 831.30.
Example 269: preparation of N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (GT-04029)
The title compound (GT-04029) (white solid, 43mg, yield 57.05%) was obtained by the method of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.04(s,1H),8.63(s,1H),7.96(dd,J＝14.1,7.5Hz,2H),7.71–7.63(m,3H),7.49(d,J＝7.6Hz,1H),7.36(dd,J＝13.7,5.7Hz,2H),7.22(dd,J＝16.2,7.2Hz,2H),7.13(d,J＝6.4Hz,1H),6.96(dd,J＝7.4,0.7Hz,1H),6.80(dd,J＝8.1,0.6Hz,1H),5.15(d,J＝8.2Hz,1H),4.59(s,1H),4.41(d,J＝28.7Hz,7H),3.86(d,J＝12.2Hz,4H),3.18(s,2H),2.92(s,3H),2.61(d,J＝14.6Hz,1H),2.43(dd,J＝13.0,4.5Hz,1H),1.98(d,J＝24.2Hz,6H).LCMS(ESI)C 41 H 38 F 5 N 8 O 7 + [M+H] + Calculated 849.27, measured 849.30.
Example 270: preparation of N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (GT-04030)
The title compound (GT-04030) (white solid, 36mg, yield 47.76%) was obtained by the method of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.03(s,1H),8.63(s,1H),8.40(dd,J＝26.9,15.0Hz,2H),8.05(d,J＝8.3Hz,1H),7.66(dd,J＝17.0,8.2Hz,2H),7.49(d,J＝7.5Hz,1H),7.36(dd,J＝13.6,5.4Hz,1H),7.25(d,J＝7.9Hz,1H),7.15(t,J＝10.2Hz,1H),6.88(ddd,J＝63.8,7.8,0.7Hz,1H),5.18–5.13(m,1H),4.50–4.37(m,8H),3.89(d,J＝2.2Hz,1H),3.85(s,3H),3.44(s,1H),3.21–3.18(m,1H),2.92(d,J＝4.3Hz,3H),2.61(d,J＝16.9Hz,1H),2.46–2.40(m,1H),1.98(dd,J＝31.3,8.6Hz,6H).LCMS(ESI)C 41 H 38 F 5 N 8 O 7 + [M+H] + Calculated 849.27, measured 849.30.
Example 271: preparation of N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (GT-04031)
The title compound (GT-04031) (white solid, 30mg, yield 39.80%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.12(s,1H),11.03(s,1H),8.63(d,J＝7.0Hz,1H),8.47–8.31(m,2H),7.67(dt,J＝15.7,6.4Hz,4H),7.49(d,J＝7.6Hz,1H),7.35(t,J＝8.8Hz,1H),7.25(d,J＝7.9Hz,1H),7.13(d,J＝6.4Hz,1H),5.13–5.09(m,1H),4.54–4.34(m,8H),3.90(s,1H),3.85(d,J＝6.9Hz,3H),3.09(dd,J＝21.3,11.1Hz,2H),2.92(s,3H),2.61(d,J＝16.5Hz,1H),2.40(dd,J＝13.1,8.9Hz,1H),1.98(dd,J＝23.6,8.1Hz,6H).LCMS(ESI)C 41 H 38 F 5 N 8 O 7 + [M+H] + Calculated 849.27, measured 849.30.
Example 272: preparation of N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (GT-04032)
The title compound (GT-04032) (white solid, 20mg, yield 27.11%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.07(s,1H),10.90(s,1H),8.63(s,1H),8.42(dd,J＝38.5,14.5Hz,2H),8.00(t,J＝7.7Hz,1H),7.83(d,J＝7.5Hz,1H),7.64(d,J＝7.7Hz,2H),7.49(d,J＝7.5Hz,1H),7.36(dd,J＝13.6,5.7Hz,1H),7.24(d,J＝7.9Hz,1H),7.13(d,J＝6.3Hz,1H),5.19(dd,J＝13.1,5.2Hz,1H),4.85(dd,J＝16.0,7.7Hz,1H),4.43(ddd,J＝20.1,18.6,10.3Hz,7H),3.91–3.87(m,1H),3.84(s,3H),3.20(d,J＝12.3Hz,2H),2.92(s,3H),2.68–2.63(m,1H),2.35(dd,J＝13.2,4.4Hz,1H),2.00(td,J＝16.4,8.2Hz,6H).LCMS(ESI)C 41 H 39 F 4 N 8 O 7 + [M+H] + Calculated 831.28, measured 831.30.
Example 273: preparation of N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide (GT-04033)
The title compound (GT-04033) (white solid, 29mg, yield 38.66%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),8.63(s,1H),8.46(d,J＝7.1Hz,1H),8.34(s,1H),8.26(s,2H),8.12(t,J＝6.1Hz,1H),8.03(d,J＝7.6Hz,1H),7.65(t,J＝7.8Hz,1H),7.49(d,J＝7.6Hz,1H),7.35(dd,J＝9.5,7.5Hz,1H),7.24(d,J＝7.9Hz,1H),7.13(d,J＝6.4Hz,1H),5.21–5.17(m,1H),4.46(dd,J＝40.9,22.0Hz,5H),3.94(ddd,J＝19.3,11.5,5.5Hz,2H),3.84(s,3H),3.10(dd,J＝21.3,10.4Hz,2H),2.92(s,3H),2.59(dd,J＝21.6,10.8Hz,2H),2.10–1.92(m,6H).LCMS(ESI)C 41 H 37 F 4 N 8 O 8 + [M+H] + Calculated 845.26, measured 845.30.
Example 274: preparation of 2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04078)
Referring to scheme 11, step 2 and the method of example 1, 2- ((2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (CAS number 2414478-49-0) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piper-ide are usedThe title compound (GT-04078) (white solid, 45mg, yield 72.47%) was obtained from pyridine-2, 6-dione (GT-03234). 1 H NMR(400MHz,DMSO)δ11.49(s,1H),11.02(s,1H),10.59(s,1H),9.73(s,1H),8.80(d,J＝4.6Hz,1H),8.29(d,J＝20.4Hz,1H),8.06–7.90(m,1H),7.89–7.70(m,3H),7.67–7.55(m,1H),7.52(t,J＝7.7Hz,1H),7.23(dd,J＝14.8,7.1Hz,2H),6.92(s,1H),6.66(d,J＝18.5Hz,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.59–4.35(m,5H),3.42(s,2H),3.15–3.05(m,2H),2.96(dt,J＝17.2,12.3Hz,2H),2.75(t,J＝5.6Hz,3H),2.62(d,J＝16.8Hz,1H),2.47–2.37(m,1H),2.32–2.17(m,5H),2.08–1.97(m,1H),1.82(d,J＝12.5Hz,2H),1.21(dd,J＝16.2,6.0Hz,6H).LCMS(ESI)C 43 H 47 F 3 N 7 O 5 + [M+H] + Calculated 798.35, measured 798.30.
Example 275: preparation of 2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04079)
Referring to the procedure of scheme 11, the title compound (GT-04079) was prepared using 2- ((2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (CAS number 2414478-49-0) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) (white solid, 41mg, yield 64.58%). 1 H NMR(400MHz,DMSO)δ11.50(s,1H),11.02(d,J＝10.2Hz,1H),10.58(s,1H),9.70(s,1H),8.79(d,J＝4.6Hz,1H),8.26(s,1H),8.09–7.96(m,1H),7.76(d,J＝7.1Hz,1H),7.70(d,J＝7.7Hz,1H),7.60(d,J＝8.1Hz,1H),7.50(dd,J＝15.3,7.5Hz,1H),7.23(dd,J＝13.7,5.7Hz,2H),6.89(s,1H),6.63(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.61(d,J＝17.6Hz,1H),4.52–4.42(m,4H),3.49(s,2H),3.14(d,J＝19.6Hz,2H),3.01–2.89(m,2H),2.74(t,J＝5.5Hz,3H),2.61(d,J＝17.4Hz,1H),2.47–2.35(m,1H),2.23(s,5H),2.06–1.99(m,1H),1.82(d,J＝12.9Hz,2H),1.19(d,J＝6.0Hz,6H).LCMS(ESI)C 43 H 46 F 4 N 7 O 5 + [M+H] + Calculated 816.34, measured 816.30.
Example 276: preparation of 2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04080)
The title compound (GT-04080) was prepared according to the method of scheme 11 (white solid, 22mg, 34.65% yield). 1 H NMR(400MHz,DMSO)δ11.43(s,1H),10.96(s,1H),10.51(s,1H),9.50(d,J＝87.1Hz,1H),8.73(d,J＝4.6Hz,1H),8.21(d,J＝17.1Hz,1H),8.07(d,J＝6.1Hz,1H),7.76–7.57(m,2H),7.53(d,J＝8.0Hz,1H),7.43(dd,J＝16.2,8.9Hz,1H),7.23–7.08(m,2H),6.83(s,1H),6.58(d,J＝14.6Hz,1H),5.09(dd,J＝13.2,5.0Hz,1H),4.47–4.29(m,5H),3.40(s,2H),3.13–3.04(m,2H),2.95–2.82(m,2H),2.68(d,J＝4.5Hz,3H),2.55(d,J＝16.8Hz,1H),2.41–2.31(m,1H),2.20–2.11(m,5H),2.00–1.90(m,1H),1.76(d,J＝12.6Hz,2H),1.12(d,J＝6.0Hz,6H).LCMS(ESI)C 43 H 46 F 4 N 7 O 5 + [M+H] + Calculated 816.34, measured 816.30.
Example 277: preparation of 2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04081)
Referring to the procedure of scheme 11, the title compound (GT-04081) (white solid, 19mg, yield 29.93%) was prepared using 2- ((2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (CAS number 2414478-49-0) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446). 1 H NMR(400MHz,DMSO)δ11.56(s,1H),11.03(s,1H),10.56(s,1H),9.61(s,1H),8.78(d,J＝4.6Hz,1H),8.28(d,J＝18.9Hz,1H),7.75(t,J＝5.4Hz,3H),7.59(t,J＝9.5Hz,1H),7.52(t,J＝7.7Hz,1H),7.28–7.13(m,2H),6.92(s,1H),6.66(d,J＝18.0Hz,1H),5.19–5.02(m,1H),4.58–4.36(m,5H),3.44(s,2H),3.15–3.06(m,2H),3.00–2.88(m,2H),2.76(d,J＝4.5Hz,3H),2.61(d,J＝16.6Hz,1H),2.46–2.34(m,1H),2.31–2.18(m,5H),2.08–1.94(m,1H),1.80(t,J＝16.4Hz,2H),1.21(t,J＝6.7Hz,6H).LCMS(ESI)C 43 H 46 F 4 N 7 O 5 + [M+H] + Calculated 816.34, measured 816.30.
Example 278: preparation of 2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04082)
The title compound (GT-04082) (white solid, 46mg, yield 74.08%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.44(s,1H),11.06(d,J＝18.1Hz,1H),10.62(s,1H),9.84(s,1H),8.82(d,J＝4.6Hz,1H),8.30(d,J＝21.0Hz,1H),8.09(d,J＝7.5Hz,1H),7.83(t,J＝9.8Hz,1H),7.77(d,J＝7.0Hz,1H),7.68–7.59(m,2H),7.54(q,J＝7.7Hz,1H),7.26(t,J＝7.5Hz,1H),7.20(s,1H),6.95(d,J＝6.3Hz,1H),6.64(s,1H),5.19(dt,J＝14.7,7.2Hz,1H),5.00(d,J＝17.6Hz,1H),4.63–4.34(m,4H),3.50(d,J＝10.8Hz,2H),3.25–3.13(m,2H),3.04–2.91(m,2H),2.75(t,J＝5.6Hz,3H),2.66(d,J＝17.1Hz,1H),2.42–2.20(m,6H),2.09–1.98(m,1H),1.80(t,J＝14.7Hz,2H),1.26–1.08(m,6H).LCMS(ESI)C 43 H 47 F 3 N 7 O 5 + [M+H] + Calculated 798.35, measured 798.30.
Example 279: preparation of 2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04083)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-04083) (white solid, 42mg, yield 66.48%) was prepared using 2- ((2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (CAS number 2414478-49-0) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5). 1 H NMR(500MHz,DMSO)δ11.50(d,J＝41.0Hz,1H),11.16(d,J＝16.8Hz,1H),10.58(s,1H),8.79(d,J＝4.6Hz,1H),8.31(s,1H),8.25(s,1H),8.18(dd,J＝13.0,12.1Hz,1H),8.07(t,J＝10.1Hz,1H),7.76(dd,J＝7.9,1.1Hz,1H),7.65–7.56(m,1H),7.53(q,J＝7.3Hz,1H),7.30–7.15(m,2H),6.92(d,J＝15.3Hz,1H),6.66(d,J＝24.2Hz,1H),5.20(dd,J＝12.8,5.4Hz,1H),4.55(d,J＝4.0Hz,2H),4.48(dq,J＝12.1,6.0Hz,1H),3.20(d,J＝10.7Hz,2H),3.14–3.06(m,2H),3.01–2.85(m,2H),2.75(t,J＝6.6Hz,3H),2.62(d,J＝18.3Hz,1H),2.58–2.52(m,1H),2.29–2.15(m,5H),2.13–2.04(m,1H),1.84(d,J＝12.7Hz,2H),1.20(d,J＝6.0Hz,6H).LCMS(ESI)C 43 H 45 F 3 N 7 O 6 + [M+H] + Calculated 812.33, measured 812.40.
Example 280: preparation of N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide (GT-03841)
The title compound (GT-03841) was obtained as a white solid (11 mg, 14.11% yield) according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.03(s,1H),10.03(s,1H),9.16(s,1H),8.90(d,J＝5.9Hz,1H),8.33(s,1H),8.21(d,J＝5.9Hz,1H),8.00(t,J＝6.8Hz,1H),7.70(d,J＝4.6Hz,2H),5.15(dd,J＝13.2,4.7Hz,1H),4.64(d,J＝10.0Hz,1H),4.56(d,J＝15.1Hz,3H),4.48–4.39(m,2H),4.28(s,2H),3.59(dd,J＝11.8,5.3Hz,3H),3.48–3.40(m,3H),3.26(d,J＝10.2Hz,1H),2.90(dd,J＝12.7,4.4Hz,1H),2.80(s,3H),2.61(d,J＝16.9Hz,1H),2.43(dd,J＝13.3,3.9Hz,1H),2.03–1.99(m,1H),1.90(dt,J＝14.1,5.2Hz,1H),1.82–1.72(m,1H).LCMS(ESI)C 38 H 38 FN 10 O 7 + [M+H] + Calculated 765.28, measured 765.30.
Example 281: preparation of N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide (GT-03842)
The title compound (GT-03842) (white solid, 11mg, 14.11% yield) was obtained according to the method of scheme 11)。 1 H NMR(400MHz,DMSO)δ11.03(s,1H),10.02(s,1H),9.15(s,1H),8.89(d,J＝5.9Hz,1H),8.32(s,1H),8.20(d,J＝5.7Hz,1H),8.10(d,J＝5.8Hz,1H),7.72–7.66(m,2H),5.15(dd,J＝13.3,4.9Hz,1H),4.50(d,J＝15.7Hz,4H),4.37(dd,J＝17.9,6.6Hz,2H),4.28(s,2H),3.60(dd,J＝9.0,4.7Hz,4H),3.48–3.40(m,4H),3.26(d,J＝9.8Hz,2H),2.91(dd,J＝11.1,6.4Hz,1H),2.80(s,3H),2.61(d,J＝16.7Hz,1H),2.46–2.37(m,1H),2.05–2.00(m,1H),1.97–1.87(m,1H),1.82–1.70(m,1H).LCMS(ESI)C 38 H 38 FN 10 O 7 + [M+H] + Calculated 765.28, measured 765.30.
Example 282: preparation of N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide (GT-03843)
The title compound (GT-03843) was obtained as a white solid (17 mg, yield 21.81%) according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.07(s,1H),9.18(s,1H),8.91(d,J＝6.0Hz,1H),8.37(s,1H),8.25(d,J＝5.7Hz,1H),7.72(d,J＝4.1Hz,3H),5.10(dd,J＝13.1,5.0Hz,1H),4.53(d,J＝17.2Hz,4H),4.40(d,J＝18.2Hz,3H),4.31–4.25(m,4H),3.63–3.57(m,2H),3.49–3.40(m,3H),3.27(d,J＝10.1Hz,2H),2.95–2.87(m,1H),2.82(s,3H),2.60(d,J＝16.2Hz,1H),2.45–2.35(m,1H),2.04–1.98(m,1H),1.90(dt,J＝12.2,6.2Hz,1H),1.78(dd,J＝8.0,4.3Hz,1H).LCMS(ESI)C 38 H 38 FN 10 O 7 + [M+H] + Calculated 765.28, measured 765.30.
Example 283: preparation of N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide (GT-03844)
The title compound (GT-03844) (white solid, 15mg, yield 19.71%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.07(s,1H),10.09(s,1H),9.19(d,J＝3.9Hz,1H),8.93(d,J＝6.0Hz,1H),8.39(s,1H),8.27(d,J＝5.9Hz,1H),8.06(t,J＝6.7Hz,1H),7.84(dd,J＝7.3,3.9Hz,1H),7.77(d,J＝34.3Hz,1H),7.65(t,J＝7.7Hz,1H),5.19(dd,J＝13.1,5.1Hz,1H),4.96–4.90(m,1H),4.58–4.43(m,6H),3.66–3.57(m,3H),3.54–3.33(m,7H),3.28(d,J＝9.9Hz,1H),3.00–2.91(m,1H),2.84(s,3H),2.65(d,J＝18.4Hz,1H),2.37–2.29(m,1H),2.04(dd,J＝11.1,5.6Hz,1H),1.91(ddd,J＝12.6,7.9,3.8Hz,1H),1.79(dt,J＝11.6,5.4Hz,1H).LCMS(ESI)C 38 H 39 N 10 O 7 + [M+H] + Calculated 747.29, measured 747.30.
Example 284: preparation of N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide (GT-03845)
The title compound (GT-03845) (white solid, 53mg, yield 68.34%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.15(s,1H),10.10(s,1H),9.20(s,1H),8.92(d,J＝6.1Hz,1H),8.39(s,1H),8.31–8.26(m,2H),8.17(d,J＝7.8Hz,1H),8.02(d,J＝7.6Hz,1H),7.71(s,1H),5.21–5.16(m,1H),4.63(s,4H),4.28(s,3H),3.76(s,1H),3.60(dd,J＝12.5,6.2Hz,2H),3.51–3.36(m,4H),3.27(d,J＝10.2Hz,2H),2.97–2.88(m,1H),2.84(s,3H),2.64–2.52(m,2H),2.11–2.04(m,1H),1.90(dt,J＝16.4,6.2Hz,1H),1.78(dd,J＝7.7,4.3Hz,1H).LCMS(ESI)C 38 H 37 N 10 O 8 + [M+H] + Calculated 761.27, measured 761.30.
Example 285: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide (GT-04036)
Referring to scheme 11, step 2 and the procedure of example 1, 6- (5-cyano-1H-pyrrolo [2, 3-b) prepared in intermediate example 74 was used ]Pyridin-1-yl) -4- (isopropylamino) -N- (piperidin-4-yl) nicotinamide (GT-D-133) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-04036) (white solid, 42mg, yield 54.89%). 1 H NMR(400MHz,DMSO)δ11.27(s,1H),11.02(s,1H),8.90(d,J＝6.8Hz,2H),8.81(dd,J＝5.3,1.9Hz,1H),8.69(t,J＝3.3Hz,2H),8.50(d,J＝3.9Hz,1H),7.95(t,J＝7.2Hz,2H),7.81(s,2H),6.93(dd,J＝7.9,3.9Hz,1H),5.14(dd,J＝13.1,5.0Hz,1H),4.53–4.36(m,4H),4.00(dt,J＝15.8,8.2Hz,2H),3.39(d,J＝11.1Hz,2H),3.22–3.04(m,2H),2.97–2.88(m,1H),2.64–2.57(m,1H),2.46–2.36(m,1H),2.06(dd,J＝25.8,8.5Hz,5H),1.29(t,J＝7.4Hz,7H).LCMS(ESI)C 36 H 38 N 9 O 4 + [M+H] + Calculated 660.30, measured 660.30.
Example 286: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide (GT-04037)
Referring to the procedure of scheme 11, 6- (5-cyano-1H-pyrrolo [2, 3-b) prepared using intermediate example 74]Pyridin-1-yl) -4- (isopropylamino) -N- (piperidin-4-yl) nicotinamide (GT-D-133) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) was prepared to give the title compound (GT-04037) (white solid, 50mg, yield 63.62%). 1 H NMR(400MHz,DMSO)δ11.34(s,1H),11.04(s,1H),8.91(d,J＝7.0Hz,1H),8.81(dd,J＝4.3,1.9Hz,1H),8.69(dd,J＝4.9,2.7Hz,2H),8.50(d,J＝3.9Hz,1H),8.04(dd,J＝15.9,8.8Hz,1H),7.96(d,J＝6.6Hz,1H),7.69(d,J＝7.7Hz,1H),6.93(dd,J＝6.6,3.9Hz,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.63–4.41(m,4H),3.85(d,J＝5.0Hz,2H),3.48(d,J＝9.4Hz,2H),3.34–3.14(m,2H),2.97–2.85(m,1H),2.67–2.56(m,1H),2.49–2.37(m,1H),2.19–1.98(m,5H),1.29(t,J＝7.8Hz,7H).LCMS(ESI)C 36 H 37 FN 9 O 4 + [M+H] + Calculated 678.29, measured 678.30.
Example 287: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide (GT-04038)
The target compound (GT-04038) was prepared according to the method of scheme 11 (white solid, 52mg, yield 66.16%). 1 H NMR(400MHz,DMSO)δ11.22(d,J＝32.6Hz,1H),11.03(s,1H),9.03–8.70(m,3H),8.68(d,J＝2.0Hz,2H),8.50(d,J＝3.9Hz,1H),8.13(dd,J＝12.7,6.1Hz,1H),7.98(d,J＝9.1Hz,1H),7.67(d,J＝8.5Hz,1H),6.93(dd,J＝7.5,3.9Hz,1H),5.15(dd,J＝13.2,4.9Hz,1H),4.44(dt,J＝28.7,17.4Hz,4H),4.03(dt,J＝16.3,9.1Hz,2H),3.46(d,J＝11.2Hz,2H),3.32–3.14(m,2H),2.97–2.87(m,1H),2.61(d,J＝17.0Hz,1H),2.48–2.38(m,1H),2.21–1.99(m,5H),1.28(d,J＝6.3Hz,6H).LCMS(ESI)C 36 H 37 FN 9 O 4 + [M+H] + Calculated 678.29, measured 678.30.
Example 288: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide (GT-04039)
Referring to the procedure of scheme 11, 6- (5-cyano-1H-pyrrolo [2, 3-b) prepared using intermediate example 74]Pyridin-1-yl) -4- (isopropylamino) -N- (piperidin-4-yl) nicotinamide (GT-D-133) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) was prepared to give the title compound (GT-04039) (white solid, 49mg, yield 62.35%). 1 H NMR(400MHz,DMSO)δ11.38(s,1H),11.03(s,1H),8.98–8.70(m,3H),8.69(dd,J＝4.3,2.1Hz,2H),8.50(d,J＝3.9Hz,1H),7.99(d,J＝7.7Hz,1H),7.73(d,J＝10.8Hz,2H),6.93(dd,J＝7.5,3.9Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.57–4.38(m,4H),4.01(dd,J＝16.6,10.7Hz,2H),3.41(d,J＝11.2Hz,2H),3.26–3.04(m,2H),2.97–2.86(m,1H),2.65–2.55(m,1H),2.46–2.33(m,1H),2.09(dd,J＝30.6,19.2Hz,5H),1.28(d,J＝6.3Hz,6H).LCMS(ESI)C 36 H 37 FN 9 O 4 + [M+H] + Calculated 678.29, measured 678.30.
Example 289: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide (GT-04040)
Referring to scheme 11, step 2 and the method of example 1, the objective was preparedThe title compound (GT-04040) (white solid, 56mg, yield 73.19%). 1 H NMR(400MHz,DMSO)δ11.23(s,1H),11.07(s,1H),8.89(d,J＝7.0Hz,1H),8.81(dd,J＝6.1,2.0Hz,1H),8.69(dd,J＝5.7,1.9Hz,2H),8.50(d,J＝3.9Hz,1H),8.06(d,J＝7.6Hz,1H),7.97(s,1H),7.83(d,J＝7.5Hz,1H),7.64(t,J＝7.6Hz,1H),6.93(dd,J＝9.0,3.9Hz,1H),5.18(dt,J＝12.7,4.3Hz,1H),5.01–4.85(m,1H),4.54(dd,J＝17.5,7.6Hz,1H),4.40(d,J＝31.8Hz,2H),4.08–3.88(m,2H),3.52–3.36(m,2H),3.21(dd,J＝21.6,10.4Hz,2H),3.01–2.91(m,1H),2.69–2.61(m,1H),2.41–2.31(m,1H),2.06(dd,J＝10.5,5.2Hz,5H),1.29(d,J＝6.3Hz,6H).LCMS(ESI)C 36 H 38 N 9 O 4 + [M+H] + Calculated 660.30, measured 660.30.
Example 290: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide (GT-04041)
Referring to scheme 11, step 2 and the procedure of example 1, 6- (5-cyano-1H-pyrrolo [2, 3-b) prepared in intermediate example 74 was used]Pyridin-1-yl) -4- (isopropylamino) -N- (piperidin-4-yl) nicotinamide (GT-D-133) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS No.: 1312023-72-5) the title compound (GT-04041) was prepared (white solid, 22mg, yield 28.16%). 1 H NMR(400MHz,DMSO)δ11.24(s,1H),11.15(s,1H),8.85–8.76(m,2H),8.71–8.63(m,2H),8.51(t,J＝4.2Hz,1H),8.28(s,1H),8.21–8.11(m,1H),8.07–7.98(m,2H),6.92(dd,J＝9.5,3.9Hz,1H),5.19(dd,J＝12.9,5.3Hz,1H),4.54(dd,J＝28.0,4.6Hz,2H),4.12–3.92(m,1H),3.81(d,J＝4.6Hz,1H),3.41(d,J＝11.7Hz,2H),3.25–3.04(m,2H),2.90(ddd,J＝12.8,10.5,6.4Hz,1H),2.67–2.52(m,2H),2.14–1.96(m,5H),1.28(d,J＝6.3Hz,6H).LCMS(ESI)C 36 H 36 N 9 O 5 + [M+H] + Calculated 674.28, measured 674.30.
Example 291: preparation of 6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- ((1 r,4 r) -4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) carbamoyl) cyclohexyl) -4- (isopropylamino) nicotinamide (GT-04077)
Referring to the procedure of scheme 56, (1 r,4 r) -4- (6- (5-cyano-1H-pyrrolo [2, 3-b) prepared in intermediate example 73]Pyridin-1-yl) -4- (isopropylamino) nicotinamide-yl) cyclohexane-1-carboxylic acid (GT-D-132) and 3- (5- (aminomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (CAS No.: 1010100-28-3) the title compound was prepared (white solid, 97mg, yield 60.48%). 1 H NMR(500MHz,DMSO)δ11.00(s,1H),8.91(s,1H),8.83(d,J＝2.0Hz,1H),8.70(d,J＝2.0Hz,1H),8.64(d,J＝2.1Hz,1H),8.58–8.43(m,3H),7.97(d,J＝3.6Hz,1H),7.68(t,J＝11.1Hz,1H),7.45(d,J＝11.4Hz,1H),7.39(d,J＝7.9Hz,1H),6.94(d,J＝3.8Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.38(dt,J＝40.4,17.4Hz,4H),3.78–3.70(m,2H),2.92(ddd,J＝17.4,13.7,5.4Hz,1H),2.64–2.57(m,1H),2.44–2.33(m,1H),2.20(td,J＝11.8,3.3Hz,1H),2.01(ddd,J＝10.3,5.2,3.1Hz,1H),1.96–1.78(m,4H),1.50(dd,J＝25.4,10.6Hz,2H),1.39(dd,J＝22.2,12.1Hz,2H),1.30(d,J＝6.3Hz,6H).LCMS(ESI)C 38 H 40 N 9 O 5 + [M+H] + Calculated 702.31, measured 702.30.
Example 292: preparation of 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (GT-04153)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-04153) was prepared using 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (CAS No. 2434842-21-2) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) (white solid, 43mg, yield 54.87%). 1 H NMR(400MHz,DMSO)δ11.52(d,J＝62.1Hz,1H),11.01(s,1H),10.01(d,J＝13.6Hz,1H),9.18–9.08(m,1H),8.46–8.13(m,1H),8.08(d,J＝6.4Hz,1H),8.00–7.89(m,1H),7.87–7.76(m,2H),7.66(d,J＝16.6Hz,1H),7.40–7.05(m,2H),5.15(dd,J＝13.2,5.0Hz,1H),4.61–4.40(m,4H),3.36(d,J＝6.7Hz,4H),3.17(t,J＝45.5Hz,3H),2.98–2.86(m,1H),2.68–2.55(m,1H),2.50–2.23(m,5H),2.04(dd,J＝19.6,14.2Hz,1H),1.15(ddd,J＝12.3,7.4,5.0Hz,1H),0.61–0.45(m,2H),0.40–0.25(m,2H).LCMS(ESI)C 36 H 38 F 2 N 9 O 5 + [M+H] + Calculated 714.29, measured 714.30.
Example 293: preparation of 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (GT-04154)
Referring to the procedure of scheme 11, the title compound (GT-04154) was prepared using 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (CAS number: 2434842-21-2) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) (white solid, 47mg, yield 58.50%). 1 H NMR(400MHz,DMSO)δ11.48(s,1H),11.02(d,J＝14.0Hz,1H),10.01(s,1H),9.34(s,1H),9.14(d,J＝6.1Hz,1H),8.17(d,J＝16.1Hz,1H),8.12–7.95(m,2H),7.76–7.64(m,2H),7.39–7.03(m,2H),5.15(dt,J＝18.5,9.2Hz,1H),4.64–4.44(m,4H),3.59(s,2H),3.37–3.08(m,5H),3.01–2.85(m,1H),2.62(d,J＝16.9Hz,1H),2.38(ddd,J＝53.9,23.4,10.5Hz,5H),2.04(dd,J＝16.0,10.5Hz,1H),1.23–1.07(m,1H),0.64–0.47(m,2H),0.39–0.28(m,2H).LCMS(ESI)C 36 H 37 F 3 N 9 O 5 + [M+H] + Calculated 732.28, found 732.30.
Example 294: preparation of 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (GT-0471)
The title compound (GT-0471) was obtained as a white solid (49 mg, yield 60.99%) by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.51(s,1H),11.02(d,J＝10.7Hz,1H),10.01(s,1H),9.41(s,1H),9.14(s,1H),8.30–8.14(m,1H),8.09(dd,J＝15.6,6.3Hz,2H),7.77–7.57(m,2H),7.43–7.04(m,2H),5.21–5.10(m,1H),4.56–4.31(m,4H),3.58(d,J＝5.3Hz,2H),3.31(d,J＝46.5Hz,5H),2.97–2.89(m,1H),2.62(d,J＝16.8Hz,1H),2.45(dd,J＝15.9,7.7Hz,3H),2.32–2.19(m,2H),2.09–1.96(m,1H),1.22–1.06(m,1H),0.61–0.48(m,2H),0.36(dq,J＝9.8,4.9Hz,2H).LCMS(ESI)C 36 H 37 F 3 N 9 O 5 + [M+H] + Calculated 732.28, found 732.30.
Example 295: preparation of 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (GT-04172)
Referring to the procedure of scheme 11, the title compound (GT-04172) was prepared using 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (CAS number: 2434842-21-2) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) (white solid, 53mg, yield 65.96%). 1 H NMR(400MHz,DMSO)δ11.69(d,J＝61.5Hz,1H),11.01(d,J＝10.3Hz,1H),10.02(d,J＝19.1Hz,1H),9.33(s,1H),9.14(d,J＝6.1Hz,1H),8.45–8.13(m,1H),8.03(dd,J＝39.5,12.6Hz,1H),7.73(dd,J＝35.1,24.9Hz,3H),7.43–7.04(m,2H),5.10(dt,J＝15.4,7.7Hz,1H),4.50(dd,J＝34.9,17.3Hz,4H),3.37–3.10(m,7H),2.90(t,J＝8.5Hz,1H),2.61(d,J＝16.8Hz,1H),2.40(dd,J＝28.2,16.1Hz,3H),2.26(d,J＝11.6Hz,2H),2.06–1.95(m,1H),1.15(dt,J＝7.4,5.1Hz,1H),0.62–0.48(m,2H),0.39–0.26(m,2H).LCMS(ESI)C 36 H 37 F 3 N 9 O 5 + [M+H] + Calculated 732.28, found 732.30.
Example 296: preparation of 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (GT-0473)
The title compound (GT-0473) was prepared according to the method of scheme 11 (white solid, 52mg, 66.35% yield). 1 H NMR(400MHz,DMSO)δ11.30(s,1H),10.97(d,J＝22.7Hz,1H),9.92(s,1H),9.17(s,1H),9.11–9.03(m,1H),8.16(d,J＝12.6Hz,1H),8.05–7.93(m,2H),7.77(d,J＝7.5Hz,1H),7.57(q,J＝7.8Hz,2H),7.32–7.02(m,2H),5.17–5.06(m,1H),4.83(d,J＝17.6Hz,1H),4.52(d,J＝22.2Hz,1H),4.41–4.26(m,2H),3.30–3.16(m,7H),2.86(dd,J＝16.6,11.7Hz,1H),2.59(d,J＝17.4Hz,1H),2.31(ddd,J＝21.3,19.4,10.7Hz,3H),2.24–2.10(m,2H),2.00(dd,J＝10.9,5.1Hz,1H),1.14–1.02(m,1H),0.48(q,J＝5.4Hz,2H),0.26(q,J＝4.8Hz,2H).LCMS(ESI)C 36 H 38 F 2 N 9 O 5 + [M+H] + Calculated 714.29, measured 714.30.
Example 297: preparation of 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (GT-04174)
Referring to scheme 11, step 2 and the procedure of example 1, the title compound (GT-04174) was prepared using 2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide (CAS No. 2434842-21-2) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS No. 1312023-72-5) (white solid, 56mg, yield 70.08%). 1 H NMR(400MHz,DMSO)δ11.49(s,1H),11.14(d,J＝12.9Hz,1H),9.97(d,J＝13.0Hz,1H),9.10(s,1H),8.32(d,J＝18.8Hz,1H),8.24–8.14(m,2H),8.07(dd,J＝17.4,7.0Hz,2H),7.54(s,1H),7.23(dd,J＝57.2,51.3Hz,2H),5.20(dd,J＝12.9,5.3Hz,1H),4.57(s,2H),3.35–3.04(m,7H),2.99–2.84(m,1H),2.60(dt,J＝11.0,9.8Hz,2H),2.47–2.19(m,4H),2.14–2.01(m,1H),1.13(dd,J＝12.2,7.4Hz,1H),0.54(q,J＝5.6Hz,2H),0.32(q,J＝4.8Hz,2H).LCMS(ESI)C 36 H 36 F 2 N 9 O 6 + [M+H] + Calculated 728.27, measured 728.30.
Example 298: preparation of N- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04267)
The title compound (GT-04267) (white solid, 52mg, yield 82.49%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,DMSO)δ11.09–10.84(m,2H),9.93(s,1H),8.94(s,1H),8.63(s,1H),8.18(d,J＝5.4Hz,1H),7.85–7.76(m,2H),7.69(dd,J＝17.6,8.7Hz,4H),7.60–7.34(m,1H),7.22(d,J＝5.1Hz,1H),7.16(dd,J＝5.4,1.4Hz,1H),7.06(d,J＝9.4Hz,2H),5.09(dd,J＝13.3,5.1Hz,1H),4.50–4.19(m,6H),3.83(d,J＝8.1Hz,2H),3.16(s,6H),2.85(dd,J＝17.2,5.8Hz,1H),2.57(dd,J＝21.4,7.6Hz,1H),2.35(dd,J＝15.0,10.7Hz,1H),2.00–1.91(m,1H).LCMS(ESI)C 39 H 36 F 5 N 10 O 5 + [M+H] + Calculated 819.27, measured 819.30.
Example 299: preparation of N- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04268)
The title compound (GT-04268) (white solid, 50mg, yield 77.61%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.96(d,J＝9.5Hz,2H),9.94(s,1H),8.94(s,1H),8.63(s,1H),8.18(d,J＝5.3Hz,1H),7.95–7.82(m,1H),7.76–7.62(m,4H),7.57–7.20(m,2H),7.16(dd,J＝5.4,1.4Hz,1H),7.06(d,J＝9.2Hz,2H),5.08(dt,J＝15.7,7.8Hz,1H),4.57–4.33(m,4H),4.25–4.15(m,2H),3.83(s,2H),3.35–3.01(m,6H),2.91–2.81(m,1H),2.54(d,J＝15.8Hz,1H),2.37(dd,J＝13.5,4.6Hz,1H),1.99–1.90(m,1H).LCMS(ESI)C 39 H 35 F 6 N 10 O 5 + [M+H] + Calculated 837.26, measured 837.30.
Example 300: preparation of N- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04269)
The title compound (GT-04269) was prepared according to the method of scheme 11 (white solid, 47mg, yield 72.95%). 1 H NMR(400MHz,DMSO)δ11.01–10.73(m,2H),9.92(s,1H),8.94(s,1H),8.63(s,1H),8.18(d,J＝5.3Hz,1H),7.95(d,J＝6.0Hz,1H),7.66(t,J＝8.2Hz,4H),7.16(ddd,J＝54.9,36.6,31.6Hz,5H),5.08(dt,J＝14.8,7.3Hz,1H),4.54–4.27(m,4H),4.24–4.13(m,2H),3.83(s,2H),3.48(d,J＝50.4Hz,3H),3.09(d,J＝22.3Hz,3H),2.92–2.81(m,1H),2.58(dd,J＝19.7,9.3Hz,1H),2.39–2.27(m,1H),2.01–1.92(m,1H).LCMS(ESI)C 39 H 35 F 6 N 10 O 5 + [M+H] + Calculated 837.26, measured 837.30.
Example 301: preparation of N- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04270)
The title compound (GT-04270) (white solid, 53mg, 82.26% yield) was obtained according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.19–10.98(m,2H),10.00(s,1H),9.01(s,1H),8.71(s,1H),8.26(d,J＝5.3Hz,1H),7.79–7.60(m,5H),7.38–7.12(m,5H),5.12(dd,J＝13.5,5.2Hz,1H),4.63–4.45(m,4H),4.32–4.21(m,2H),3.90(s,2H),3.37–3.13(m,6H),2.92(dd,J＝17.7,6.0Hz,1H),2.61(d,J＝15.6Hz,1H),2.43–2.34(m,1H),2.02(d,J＝4.7Hz,1H).LCMS(ESI)C 39 H 35 F 6 N 10 O 5 + [M+H] + Calculated 837.26, measured 837.30.
Example 302: preparation of N- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04271)
The title compound (GT-04271) (white solid, 28mg, yield 44.42%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.97(d,J＝32.4Hz,2H),9.93(s,1H),8.94(s,1H),8.63(s,1H),8.18(d,J＝5.3Hz,1H),7.93(d,J＝7.7Hz,1H),7.79(d,J＝7.3Hz,1H),7.67(d,J＝9.1Hz,3H),7.63–7.51(m,2H),7.36–7.04(m,5H),5.19–5.08(m,1H),4.79(d,J＝17.5Hz,1H),4.52–4.39(m,3H),4.19(dt,J＝16.5,8.1Hz,2H),3.84(s,2H),3.23(s,6H),2.87(d,J＝12.7Hz,1H),2.63–2.56(m,1H),2.34–2.26(m,1H),2.02–1.95(m,1H).LCMS(ESI)C 39 H 36 F 5 N 10 O 5 + [M+H] + Calculated 819.27, measured 819.30.
Example 303: preparation of N- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04272)
The title compound (white solid, 58mg, 90.45% yield) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.20–10.97(m,2H),10.00(s,1H),9.01(s,1H),8.71(s,1H),8.25(d,J＝4.8Hz,2H),8.10(dd,J＝21.3,7.7Hz,2H),7.72(dd,J＝17.4,7.9Hz,3H),7.44–7.11(m,5H),5.20(dd,J＝12.8,5.3Hz,1H),4.62(s,2H),4.26(dt,J＝16.5,8.1Hz,2H),3.93(s,2H),3.22(s,6H),2.99–2.85(m,1H),2.70–2.56(m,2H),2.13–2.04(m,1H).LCMS(ESI)C 39 H 34 F 5 N 10 O 6 + [M+H] + Calculated 833.25, measured 833.30.
Example 304: preparation of N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide (GT-03692)
Referring to scheme 11, step 2 and the procedure of example 1, N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4 '- (piperazin-1-ylmethyl) - [1,1' -biphenyl) prepared in intermediate example 85 was used ]The title compound (GT-03692) was prepared from (GT-S-10) 3-carboxamide and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-030334) (white solid, 59.00mg, yield 79.85%). 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.01(s,1H),10.77(s,1H),9.72(s,1H),8.48(s,1H),8.02(s,2H),7.84(dd,J＝33.8,7.6Hz,4H),7.62(dd,J＝9.1,4.2Hz,1H),7.46–7.25(m,2H),5.92(s,1H),5.14(dd,J＝12.8,4.5Hz,1H),4.60(d,J＝12.5Hz,2H),4.54–4.47(m,2H),4.46–4.36(m,3H),4.31(d,J＝3.7Hz,2H),4.07–3.73(m,7H),3.63–3.49(m,3H),3.24(s,2H),3.14–3.05(m,3H),2.92(t,J＝13.1Hz,1H),2.63(s,3H),2.50(s,3H),2.46–2.37(m,3H),2.23(s,3H),2.13(s,3H),2.03(dd,J＝17.3,11.5Hz,2H),1.32(s,3H).LCMS(ESI)C 48 H 58 N 7 O 6 + [M+H] + Calculated 828.44, measured 828.50.
Example 305: preparation of 3- (5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03793)
Referring to scheme 11, step 2 and the procedure of example 1, (R) -6- (2- (3-fluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) imidazo [1,2-b ] prepared in intermediate example 91]Pyridazine (GT-S-17) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-03793) (white solid, 43mg, yield 54.51%). 1 H NMR(400MHz,DMSO)δ11.01(s,1H),8.12(s,1H),7.89(d,J＝9.9Hz,2H),7.78(dd,J＝16.6,7.5Hz,2H),7.64–7.48(m,2H),7.38(d,J＝6.3Hz,1H),7.16(d,J＝7.6Hz,2H),7.03(t,J＝8.2Hz,1H),6.82(t,J＝10.3Hz,2H),5.18–5.11(m,2H),4.44(dd,J＝52.7,17.6Hz,6H),3.98(dd,J＝9.7,4.9Hz,1H),3.66(dd,J＝17.1,7.9Hz,2H),3.16–3.03(m,2H),3.01–2.85(m,2H),2.61(d,J＝17.2Hz,1H),2.49–2.35(m,3H),2.27–1.91(m,4H),1.89–1.81(m,1H).LCMS(ESI)C 39 H 39 FN 9 O 3 + [M+H] + Calculated 700.31, measured 700.30.
Example 306: preparation of 3- (5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03794)
Referring to scheme 11, step 2 and the procedure of example 1, (R) -1- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1, 2-b) prepared in intermediate example 92 is used ]Pyridazin-3-yl) pyridin-2-yl) -N-methylpiperidin-4-amine (GT-S-18) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piper-dinePyridine-2, 6-dione (GT-03234) prepared the title compound (white solid, 20mg, yield 28.53%). 1 H NMR(400MHz,DMSO)δ11.47(s,1H),11.02(s,1H),8.59(s,1H),8.21(d,J＝5.8Hz,1H),7.99(s,1H),7.85(s,1H),7.79(d,J＝7.9Hz,1H),7.41(dd,J＝13.8,7.7Hz,2H),7.19(d,J＝7.6Hz,2H),7.13–6.94(m,3H),5.23(d,J＝4.7Hz,1H),5.13(dd,J＝13.1,4.9Hz,1H),4.60(d,J＝10.7Hz,3H),4.53–4.47(m,2H),4.41–4.33(m,4H),3.72(dd,J＝16.6,8.2Hz,2H),3.53(s,1H),2.96–2.80(m,3H),2.63(s,2H),2.46–2.34(m,2H),2.26(d,J＝11.8Hz,1H),2.03(dd,J＝17.8,8.5Hz,3H),1.92(d,J＝7.5Hz,1H),1.84–1.71(m,2H).LCMS(ESI)C 41 H 43 FN 9 O 3 + [M+H] + Calculated 728.34, measured 728.40.
Example 307: preparation of 3- (4-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03865)
Referring to the procedure of scheme 11, (R) -6- (2- (3-fluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) imidazo [1,2-b ] prepared in intermediate example 91]Pyridazine (GT-S-17) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03865) (white solid, 67mg, yield 82.80%). 1 H NMR(400MHz,DMSO)δ11.04(s,1H),8.44(s,1H),8.08(d,J＝9.9Hz,1H),8.00(t,J＝6.7Hz,1H),7.70(d,J＝7.7Hz,1H),7.68–7.43(m,2H),7.42–7.33(m,1H),7.18(d,J＝8.0Hz,3H),7.04(t,J＝8.3Hz,1H),6.93(d,J＝8.3Hz,1H),5.23–5.13(m,2H),4.65–4.40(m,6H),4.06–4.00(m,1H),3.70(dd,J＝17.1,8.4Hz,2H),3.26–3.12(m,4H),3.03–2.84(m,2H),2.61(d,J＝17.2Hz,1H),2.48–2.38(m,2H),2.09–1.99(m,3H),1.94–1.86(m,1H).LCMS(ESI)C 39 H 38 F 2 N 9 O 3 + [M+H] + Calculated 718.30, measured 718.30.
Example 308: preparation of 3- (6-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03866)
The title compound (GT-03866) (white solid, 30.00mg, yield 37.07%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.03(s,1H),8.53(s,1H),8.14(d,J＝6.3Hz,2H),7.75–7.43(m,3H),7.40(d,J＝6.6Hz,1H),7.18(d,J＝8.3Hz,3H),7.05(t,J＝8.0Hz,1H),6.95(d,J＝8.4Hz,1H),5.24–5.12(m,2H),4.44(dd,J＝52.6,18.6Hz,6H),4.06–4.01(m,1H),3.71(d,J＝8.7Hz,2H),3.20(ddd,J＝41.4,26.6,14.6Hz,4H),3.06–2.79(m,2H),2.61(d,J＝16.8Hz,1H),2.49–2.32(m,2H),2.10–1.99(m,3H),1.97–1.83(m,1H).LCMS(ESI)C 39 H 38 F 2 N 9 O 3 + [M+H] + Calculated 718.30, measured 718.30.
Example 309: preparation of 3- (7-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03867)
Referring to the procedure of scheme 11, (R) -6- (2- (3-fluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) imidazo [1,2-b ] prepared in intermediate example 91]Pyridazine (GT-S-17) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) gave the title compound (white solid, 78mg, yield 96.39%). 1 H NMR(400MHz,DMSO)δ11.98(s,1H),11.03(s,1H),8.54(s,1H),8.14(d,J＝9.6Hz,1H),7.82–7.47(m,4H),7.40(d,J＝6.4Hz,1H),7.18(d,J＝8.2Hz,3H),7.04(d,J＝8.1Hz,1H),6.96(d,J＝8.5Hz,1H),5.22(d,J＝6.8Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.49(t,J＝26.5Hz,6H),4.07–4.02(m,1H),3.74–3.68(m,2H),3.25–3.04(m,4H),3.01–2.85(m,2H),2.60(d,J＝16.8Hz,1H),2.48–2.33(m,2H),2.09–1.99(m,3H),1.94–1.87(m,1H).LCMS(ESI)C 39 H 38 F 2 N 9 O 3 + [M+H] + Calculated 718.30, measured 718.30.
Example 310: preparation of 3- (4- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03868)
The title compound (GT-03868) (white solid, 72mg, yield 91.27%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.70(s,1H),11.04(s,1H),8.38(s,1H),8.05(t,J＝7.5Hz,2H),7.83(d,J＝7.6Hz,1H),7.70–7.50(m,3H),7.39(td,J＝8.0,6.5Hz,1H),7.24–7.09(m,3H),7.06–7.00(m,1H),6.95–6.87(m,1H),5.22–5.15(m,2H),4.93(d,J＝17.7Hz,1H),4.65–4.30(m,6H),4.05–3.99(m,1H),3.70(dd,J＝17.5,8.2Hz,2H),3.25–3.16(m,3H),3.03–2.82(m,2H),2.63(d,J＝18.1Hz,2H),2.35–2.26(m,1H),2.09–2.01(m,3H),1.94–1.83(m,1H).LCMS(ESI)C 39 H 39 FN 9 O 3 + [M+H] + Calculated 700.31, measured 700.30.
Example 311: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione (GT-03869)
Referring to the procedure of scheme 11, (R) -6- (2- (3-fluorophenyl) pyrrolidin-1-yl) -3- (6- (piperazin-1-yl) pyridin-2-yl) imidazo [1,2-b ] prepared in intermediate example 91]Pyridazine (GT-S-17) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5) gave the title compound (GT-03869) (white solid, 66mg, yield 82.03%). 1 H NMR(400MHz,DMSO)δ11.97(s,1H),11.15(s,1H),8.52(s,1H),8.29(s,1H),8.15(dd,J＝17.0,9.0Hz,2H),8.03(d,J＝7.6Hz,1H),7.74–7.45(m,2H),7.44–7.25(m,2H),7.18(d,J＝8.0Hz,2H),7.05(t,J＝8.0Hz,1H),6.96(d,J＝8.6Hz,1H),5.27–5.16(m,2H),4.55(d,J＝32.2Hz,5H),4.15–3.96(m,2H),3.72(dd,J＝16.2,6.8Hz,2H),3.19–3.03(m,3H),2.92(dd,J＝9.6,6.5Hz,1H),2.59(dd,J＝21.9,10.9Hz,3H),2.12–2.02(m,3H),1.90(dd,J＝11.8,4.8Hz,1H).LCMS(ESI)C 39 H 37 FN 9 O 4 + [M+H] + Calculated 714.29, measured 714.30.
Example 312: preparation of 2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione (GT-03897)
Referring to scheme 11, step 2 and the procedure of example 1, (R) -1- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1, 2-b) prepared in intermediate example 92 is used]Pyridazin-3-yl) pyridin-2-yl) -N-methylpiperidin-4-amine (GT-S-18) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS No.: 1312023-72-5) to give the objective compound (GT-03897) (white solid, 30.00mg, yield 41.09%). 1 H NMR(400MHz,DMSO)δ11.14(s,1H),8.57(s,1H),8.34(s,1H),8.24(d,J＝7.6Hz,1H),8.18(d,J＝10.1Hz,1H),8.00(d,J＝7.7Hz,1H),7.54(s,1H),7.40(dd,J＝14.2,7.9Hz,2H),7.18(d,J＝8.2Hz,2H),7.07(dd,J＝18.0,10.0Hz,2H),6.99(d,J＝8.4Hz,1H),5.25–5.16(m,2H),4.64(dd,J＝21.0,10.0Hz,3H),4.11–4.01(m,2H),3.72(d,J＝9.4Hz,2H),3.56(s,2H),2.91–2.82(m,3H),2.58(d,J＝3.7Hz,4H),2.32(dd,J＝13.6,9.2Hz,2H),2.07(dd,J＝5.8,3.5Hz,3H),1.92(dd,J＝11.8,4.2Hz,1H),1.83–1.72(m,2H).LCMS(ESI)C 41 H 41 FN 9 O 4 + [M+H] + Calculated 742.32, measured 742.30.
Example 313: preparation of 4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (GT-03990)
The title compound (GT-03990) (white solid, 15mg, yield 29.9%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ9.55(s,1H),9.19(d,J＝8.2Hz,1H),8.83(d,J＝5.4Hz,1H),8.49(d,J＝5.3Hz,1H),8.20(s,1H),8.05(dd,J＝8.2,5.7Hz,1H),7.97(d,J＝8.2Hz,2H),7.82(d,J＝7.8Hz,1H),7.67(s,1H),7.59(d,J＝8.1Hz,3H),7.46(d,J＝5.4Hz,1H),7.29–7.17(m,2H),5.07(dd,J＝13.3,5.1Hz,1H),4.46(q,J＝17.4Hz,6H),2.86–2.62(m,5H),2.40(dt,J＝13.7,8.7Hz,1H),2.23(s,3H),2.13–2.02(m,1H).LCMS(ESI)C 39 H 37 N 8 O 4 + [M+H] + Calculated 681.29, measured 681.3.
Example 314: preparation of N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04236)
The title compound (GT-04236) (pale yellow solid, 35mg, yield 44.91%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,MeOD)δ8.89(d,J＝4.4Hz,1H),8.40–8.29(m,2H),8.25–8.15(m,2H),8.10–8.02(m,1H),7.96(dd,J＝17.8,7.8Hz,3H),7.77–7.66(m,2H),7.62(d,J＝8.8Hz,1H),7.54(d,J＝8.3Hz,1H),5.25(dd,J＝13.2,5.1Hz,1H),4.90(s,1H),4.71(d,J＝17.2Hz,1H),4.55(t,J＝11.0Hz,2H),3.88–3.64(m,5H),3.37(d,J＝15.4Hz,4H),3.28(s,4H),3.05–2.91(m,1H),2.84(d,J＝16.0Hz,1H),2.69(s,3H),2.57(s,3H),2.28(s,3H).LCMS(ESI)C 46 H 45 F 3 N 9 O 4 + [M+H] + Calculated 844.35, measured 844.4.
Example 315: preparation of N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04237)
Referring to scheme 11, step 2 and the procedure of example 1, 3- (imidazo [1,2-b ] prepared in example 71 is used as an intermediate]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-112) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) the title compound (GT-04237) was prepared (pale yellow solid, 18mg, yield 23.10%). 1 H NMR(400MHz,MeOD)δ9.01(d,J＝4.5Hz,1H),8.51(s,1H),8.44(d,J＝9.6Hz,1H),8.21(d,J＝16.8Hz,2H),8.06(d,J＝8.8Hz,1H),7.97(t,J＝8.1Hz,2H),7.90–7.81(m,2H),7.77(d,J＝7.3Hz,1H),7.63(d,J＝8.3Hz,1H),7.55(d,J＝8.1Hz,1H),5.20(d,J＝13.7Hz,1H),4.61(dd,J＝25.2,18.1Hz,4H),3.76(dd,J＝13.1,6.6Hz,6H),3.25(dd,J＝14.8,7.4Hz,7H),2.95(s,1H),2.82(d,J＝15.9Hz,1H),2.70(s,3H),2.56(s,3H),2.24(s,3H).LCMS(ESI)C 46 H 45 F 3 N 9 O 4 + [M+H] + Calculated 844.35, measured 844.3.
Example 316: preparation of N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04238)
Referring to the procedure of scheme 11, 3- (imidazo [1,2-b ] prepared in intermediate example 71 is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-112) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-04238) (light yellow solid, 34mg, yield 42.79%). 1 H NMR(400MHz,MeOD)δ9.05(d,J＝3.8Hz,1H),8.55(s,1H),8.47(d,J＝9.4Hz,1H),8.23(s,1H),8.20(s,1H),8.06(d,J＝8.3Hz,1H),7.99(d,J＝9.6Hz,1H),7.92–7.84(m,2H),7.81(d,J＝7.8Hz,1H),7.63(d,J＝8.7Hz,1H),7.56(d,J＝8.1Hz,1H),5.25–5.18(m,1H),4.68(dd,J＝29.2,17.2Hz,4H),3.74(dd,J＝13.1,6.8Hz,6H),3.31–3.14(m,7H),2.93(d,J＝13.6Hz,1H),2.84(s,1H),2.70(s,3H),2.57(s,3H),2.24(s,3H).LCMS(ESI)C 46 H 44 F 4 N 9 O 4 + [M+H] + Calculated 862.34, measured 862.3.
Example 317: preparation of N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04239)
The title compound (GT-04239) (pale yellow solid, 36mg, yield 45.31%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.98(d,J＝3.4Hz,1H),8.47(s,1H),8.41(d,J＝9.4Hz,1H),8.21(d,J＝14.8Hz,2H),8.10–8.02(m,1H),7.97(t,J＝5.9Hz,2H),7.81(dd,J＝9.3,4.5Hz,1H),7.72(d,J＝8.6Hz,1H),7.63(d,J＝8.6Hz,1H),7.55(d,J＝8.2Hz,1H),5.20(dd,J＝13.4,5.1Hz,1H),4.67–4.49(m,4H),3.77(t,J＝25.9Hz,5H),3.34(s,4H),3.27(d,J＝11.9Hz,4H),3.01–2.88(m,1H),2.82(d,J＝15.6Hz,1H),2.70(s,3H),2.55(dd,J＝19.6,6.7Hz,3H),2.23(s,3H).LCMS(ESI)C 46 H 44 F 4 N 9 O 4 + [M+H] + Calculated 862.34, measured 862.4.
Example 318: preparation of N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide (GT-04240)
Referring to the procedure of scheme 11, 3- (imidazo [1,2-b ] prepared in intermediate example 71 is used]Pyridazin-3-ylethynyl) -4-methyl-N- (4- (4- (piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) benzamide (GT-D-112) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) the title compound (GT-04240) was prepared (light yellow solid, 34mg, 42.79% yield). 1 H NMR(400MHz,MeOD)δ9.06(d,J＝4.7Hz,1H),8.57(s,1H),8.48(d,J＝8.1Hz,1H),8.21(d,J＝18.7Hz,2H),8.06(d,J＝6.2Hz,1H),8.00(d,J＝8.4Hz,1H),7.91(dd,J＝9.4,4.5Hz,1H),7.69(s,1H),7.63(d,J＝8.5Hz,1H),7.54(dd,J＝16.5,8.8Hz,2H),5.18(dd,J＝13.3,5.0Hz,1H),4.61(dd,J＝29.6,21.3Hz,4H),3.75(d,J＝12.0Hz,5H),3.35(s,4H),3.29(s,4H),3.02–2.89(m,1H),2.81(d,J＝15.5Hz,1H),2.70(s,3H),2.55(s,3H),2.23(s,3H).LCMS(ESI)C 46 H 44 F 4 N 9 O 4 + [M+H] + Calculated 862.34, measured 862.3.
Example 319: preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide (GT-04019)
The title compound (GT-04019) (white solid, 27mg, yield 42.66%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.89(s,1H),10.53(s,1H),8.80(d,J＝2.4Hz,1H),8.40(d,J＝2.4Hz,1H),7.91(dd,J＝6.9,2.2Hz,3H),7.84–7.77(m,3H),7.35(d,J＝9.1Hz,2H),6.73(dd,J＝2.0,1.0Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.60–4.47(m,2H),4.44–4.29(m,3H),3.48–3.37(m,2H),2.96–2.89(m,1H),2.79(dd,J＝21.7,11.1Hz,2H),2.64–2.57(m,4H),2.47–2.34(m,1H),2.17(dd,J＝24.0,10.7Hz,2H),2.05–1.98(m,1H),1.95–1.79(m,2H).LCMS(ESI)C 36 H 36 ClF 2 N 8 O 5 + [M+H] + Calculated 733.24, measured 733.30.
Example 320: preparation of the following Compounds
Referring to scheme 11, step 2 and example 1, one of the intermediates prepared in intermediate example 94 was reacted with 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234), respectively, to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
One of the two target compounds above (GT-03795) (white solid, 30mg, yield 33%): 1 H NMR(400MHz,MeOD)δ7.93(d,J＝7.8Hz,1H),7.80(s,1H),7.72(d,J＝7.9Hz,1H),7.17–7.10(m,3H),6.74–6.65(m,5H),6.56–6.52(m,2H),6.35(d,J＝2.1Hz,1H),6.30(dd,J＝8.3,2.4Hz,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.88–4.88(m,1H),4.61–4.50(m,4H),4.40(t,J＝11.1Hz,1H),4.23(d,J＝5.1Hz,1H),4.19(d,J＝7.8Hz,1H),3.78–3.68(m,2H),3.58–3.51(m,2H),3.38–3.32(m,2H),3.05–2.87(m,3H),2.84–2.76(m,1H),2.52(qd,J＝13.1,4.7Hz,1H),2.23–2.15(m,1H).LCMS(ESI)m/z:C 39 H 39 N 4 O 5 + [M+H] + calculated 643.29; found, 643.3.
Another target compound (GT-03774) (white solid, 54mg, yield 64.94%): 1 H NMR(400MHz,DMSO)δ11.35(s,1H),11.00(s,1H),7.90(s,1H),7.80(dd,J＝16.7,7.8Hz,2H),7.18–7.08(m,3H),6.76(dd,J＝6.2,3.1Hz,2H),6.65(dd,J＝8.4,5.3Hz,3H),6.43(d,J＝8.6Hz,2H),6.35–6.24(m,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝17.7Hz,3H),4.40–4.29(m,2H),4.19(dd,J＝10.3,3.8Hz,2H),3.65(d,J＝10.7Hz,2H),3.54(d,J＝4.7Hz,1H),3.34(d,J＝9.4Hz,2H),3.16–3.02(m,4H),2.97–2.88(m,1H),2.61(d,J＝16.9Hz,1H),2.46–2.35(m,1H),2.04–1.93(m,1H).LCMS(ESI)C 39 H 39 N 4 O 5 + [M+H] + calculated 643.28, measured 643.30.
Example 321: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 94 was reacted with 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03796) (white solid, 39mg, yield 42%): 1 H NMR(400MHz,MeOD)δ7.84–7.74(m,2H),7.15–7.07(m,3H),6.77–6.65(m,5H),6.54(d,J＝8.4Hz,2H),6.35(d,J＝2.1Hz,1H),6.30(dd,J＝8.3,2.2Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.87–4.85(m,1H),4.71–4.55(m,4H),4.40(t,J＝11.1Hz,1H),4.23(d,J＝5.2Hz,1H),4.19(d,J＝8.0Hz,1H),3.81–3.38(m,6H),3.11–2.86(m,3H),2.84–2.73(m,1H),2.53(qd,J＝13.2,4.7Hz,1H),2.25–2.15(m,1H).LCMS(ESI)m/z:C 39 H 38 FN 4 O 5 + [M+H] + calculated 661.28; found 661.3.
Another target compound (GT-03784) (white solid, 68mg, yield 79.55%): 1 H NMR(400MHz,DMSO)δ11.35(s,1H),11.04(s,1H),7.96(t,J＝6.9Hz,1H),7.69(d,J＝7.7Hz,1H),7.18–7.08(m,3H),6.76(dd,J＝6.1,3.0Hz,2H),6.65(t,J＝8.0Hz,3H),6.43(d,J＝8.6Hz,2H),6.34–6.21(m,2H),5.15(dd,J＝13.2,5.0Hz,1H),4.62–4.41(m,4H),4.32(t,J＝11.1Hz,1H),4.19(dd,J＝10.5,3.7Hz,2H),3.66(d,J＝11.4Hz,2H),3.56–3.48(m,3H),3.18(s,2H),3.05(t,J＝12.7Hz,2H),2.97–2.85(m,1H),2.61(dd,J＝15.8,1.6Hz,1H),2.48–2.38(m,1H),2.01(dt,J＝10.2,3.7Hz,1H).LCMS(ESI)C 39 H 38 FN 4 O 5 + [M+H] + calculated 661.27, measured 661.30.
Example 322: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 94 was reacted with 3- (6-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione, respectively, to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
One of the two target compounds above (GT-03797) (white solid, 53mg, yield 58%): 1 H NMR(400MHz,MeOD)δ7.86(d,J＝6.0Hz,1H),7.69(d,J＝8.5Hz,1H),7.14–7.07(m,3H),6.75–6.65(m,5H),6.54(d,J＝8.7Hz,2H),6.35(d,J＝2.4Hz,1H),6.30(dd,J＝8.3,2.5Hz,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.66–4.46(m,5H),4.40(t,J＝11.1Hz,1H),4.23(d,J＝5.2Hz,1H),4.19(dd,J＝10.1,2.8Hz,1H),3.76–3.36(m,6H),3.09–2.85(m,3H),2.83–2.75(m,1H),2.51(qd,J＝13.4,4.9Hz,1H),2.24–2.15(m,1H).LCMS(ESI)m/z:C 39 H 55 FN 4 O 5 + [M+H] + calculated 661.28; found, 661.3.
Another target compound (GT-03785) (white solid, 69mg, yield 80.72%): 1 H NMR(400MHz,DMSO)δ11.46(s,1H),11.03(s,1H),8.08(d,J＝6.1Hz,1H),7.67(d,J＝8.4Hz,1H),7.19–7.08(m,3H),6.77(d,J＝3.2Hz,2H),6.65(dd,J＝8.2,6.5Hz,3H),6.43(d,J＝8.5Hz,2H),6.35–6.24(m,2H),5.14(dd,J＝13.2,5.0Hz,1H),4.49(d,J＝17.4Hz,3H),4.33(dd,J＝23.8,14.0Hz,2H),4.19(dd,J＝10.6,3.5Hz,2H),3.66(d,J＝12.4Hz,2H),3.44(d,J＝13.1Hz,3H),3.19(s,2H),3.07(t,J＝11.9Hz,2H),2.98–2.85(m,1H),2.60(d,J＝16.4Hz,1H),2.48–2.35(m,1H),2.07–1.96(m,1H).LCMS(ESI)C 39 H 38 FN 4 O 5 + [M+H] + calculated 661.27, measured 661.30.
Example 323: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 94 was reacted with 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03798) (white solid, 42mg, yield 46%): 1 H NMR(400MHz,MeOD)δ7.60(s,1H),7.45(d,J＝9.5Hz,1H),7.11(dd,J＝5.1,1.9Hz,3H),6.75–6.65(m,5H),6.54(d,J＝8.7Hz,2H),6.35(d,J＝2.4Hz,1H),6.30(dd,J＝8.3,2.5Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.84–4.77(m,1H),4.65–4.56(m,2H),4.52(s,2H),4.41(t,J＝11.1Hz,1H),4.24(d,J＝5.1Hz,1H),4.19(dd,J＝10.6,2.2Hz,1H),3.86–3.66(m,2H),3.57–3.52(m,2H),3.30–3.22(m,2H),3.08–2.86(m,3H),2.83–2.74(m,1H),2.50(qd,J＝13.1,4.5Hz,1H),2.24–2.14(m,1H).LCMS(ESI)m/z:C 39 H 38 FN 4 O 5 + [M+H] + calculated 661.28; found 661.3.
Another target compound (GT-03786) (white solid, 68mg, yield 79.55%): 1 H NMR(400MHz,DMSO)δ11.56(s,1H),11.03(s,1H),7.69(d,J＝11.8Hz,2H),7.17–7.11(m,3H),6.76(dd,J＝6.3,2.8Hz,2H),6.65(dd,J＝8.2,6.6Hz,3H),6.43(d,J＝8.6Hz,2H),6.33–6.25(m,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.57–4.40(m,4H),4.37–4.30(m,1H),4.19(dd,J＝10.4,3.6Hz,2H),3.65(d,J＝8.5Hz,2H),3.56–3.48(m,2H),3.36(d,J＝8.0Hz,2H),3.09(d,J＝8.2Hz,3H),2.96–2.87(m,1H),2.60(d,J＝17.2Hz,1H),2.44–2.31(m,1H),2.00(dd,J＝12.1,6.8Hz,1H).LCMS(ESI)C 39 H 38 FN 4 O 5 + [M+H] + calculated 661.27, measured 661.30.
Example 324: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 94 was reacted with 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number 1312023-72-5) to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03801) (white solid, 40mg, yield 44%): 1 H NMR(400MHz,DMSO)δ11.14(s,1H),9.30(s,1H),8.21(s,1H),8.09(d,J＝7.7Hz,1H),8.04(d,J＝7.7Hz,1H),7.17–7.10(m,3H),6.77(d,J＝2.7Hz,2H),6.65(t,J＝9.0Hz,3H),6.44(d,J＝8.6Hz,2H),6.31(d,J＝2.3Hz,1H),6.27(dd,J＝8.3,2.4Hz,1H),5.21–5.15(m,1H),4.57(s,2H),4.32(t,J＝11.2Hz,1H),4.21(d,J＝4.3Hz,2H),3.74–3.62(m,3H),3.56–3.49(m,2H),3.18–3.08(m,2H),3.01–2.81(m,5H),2.07–2.03(m,2H).LCMS(ESI)m/z:C 39 H 37 N 4 O 6 + [M+H] + calculated 657.27; found 657.3.
Another target compound (GT-03788) (white solid, 17mg, yield 20.01%): 1 H NMR(400MHz,DMSO)δ11.35(s,1H),11.15(s,1H),8.25(s,1H),8.13(d,J＝7.8Hz,1H),8.03(d,J＝7.6Hz,1H),7.86–7.74(m,1H),7.18–7.11(m,3H),6.76(dd,J＝6.0,2.8Hz,2H),6.65(t,J＝8.3Hz,3H),6.43(d,J＝8.5Hz,2H),6.33–6.24(m,2H),5.18(dd,J＝12.8,5.4Hz,1H),4.56(s,2H),4.32(t,J＝11.2Hz,1H),4.19(dd,J＝10.1,3.7Hz,2H),3.67(d,J＝11.7Hz,2H),3.57–3.49(m,2H),3.17–2.98(m,4H),2.92–2.86(m,1H),2.67–2.52(m,3H),2.06(dd,J＝10.4,5.3Hz,1H).LCMS(ESI)C 39 H 37 N 4 O 6 + [M+H] + calculated 657.26, measured 657.30.
Example 325: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 94 was reacted with 3- (4- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03802) (white solid, 49mg, yield 54%): 1 H NMR(400MHz,MeOD)δ7.95(d,J＝7.4Hz,1H),7.88(d,J＝7.4Hz,1H),7.70(t,J＝7.7Hz,1H),7.14–7.09(m,3H),6.76–6.70(m,4H),6.67(d,J＝8.3Hz,1H),6.54(d,J＝8.6Hz,2H),6.36(d,J＝2.4Hz,1H),6.30(dd,J＝8.3,2.4Hz,1H),5.22(dd,J＝13.3,5.2Hz,1H),4.92–4.87(m,1H),4.77(d,J＝17.3Hz,1H),4.66(d,J＝17.4Hz,1H),4.51(s,2H),4.40(t,J＝11.1Hz,1H),4.23(d,J＝5.3Hz,1H),4.18(dd,J＝10.7,2.5Hz,1H),3.73–3.42(m,6H),3.17–3.00(m,2H),2.98–2.88(m,1H),2.85–2.75(m,1H),2.52(qd,J＝13.2,4.7Hz,1H),2.27–2.16(m,1H).LCMS(ESI)m/z:C 39 H 39 N 4 O 5 + [M+H] + calculated 643.29; found 643.3.
Another target compound (GT-03787) (white solid, 55mg, yield 66.15%): 1 H NMR(400MHz,DMSO)δ11.38(s,1H),11.07(s,1H),8.02(d,J＝7.5Hz,1H),7.83(d,J＝7.5Hz,1H),7.63(t,J＝7.6Hz,1H),7.20–7.09(m,3H),6.82–6.72(m,2H),6.65(dd,J＝8.2,6.5Hz,3H),6.43(d,J＝8.5Hz,2H),6.37–6.24(m,2H),5.18(dd,J＝13.2,5.1Hz,1H),4.89(d,J＝17.5Hz,1H),4.52(d,J＝17.6Hz,1H),4.42(s,2H),4.32(t,J＝11.1Hz,1H),4.19(dd,J＝10.5,3.6Hz,2H),3.66(d,J＝11.8Hz,2H),3.56–3.49(m,3H),3.25–3.05(m,4H),3.00–2.88(m,1H),2.64(d,J＝16.9Hz,1H),2.41–2.23(m,1H),2.10–1.98(m,1H).LCMS(ESI)C 39 H 39 N 4 O 5 + [M+H] + calculated 643.28, measured 643.30.
Example 326: preparation of the following Compounds
Referring to scheme 11, step 2 and example 1, one of the intermediates prepared in intermediate example 93 was reacted with 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234), respectively, to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03949) (white solid, 46mg, yield 51%): 1 H NMR(400MHz,DMSO)δ11.00(s,1H),10.71(s,1H),9.12(s,1H),7.89–7.81(m,2H),7.73(d,J＝8.2Hz,1H),7.19–7.07(m,3H),6.83(d,J＝6.6Hz,2H),6.66–6.53(m,4H),6.48(dd,J＝8.3,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.14(dd,J＝13.4,5.1Hz,1H),4.56–4.45(m,3H),4.38(d,J＝17.7Hz,1H),4.16(d,J＝4.9Hz,1H),3.68–3.60(m,2H),3.35–3.32(m,1H),3.27–3.05(m,3H),3.00–2.84(m,5H),2.64–2.58(m,1H),2.45–2.36(m,1H),2.12–1.96(m,2H),1.77–1.66(m,1H).LCMS(ESI)m/z:C 40 H 41 N 4 O 4 + [M+H] + calculated 641.31; found 641.3.
Another target compound (GT-03850) (white solid, 63.00mg, yield 75.61%): 1 H NMR(400MHz,DMSO)δ11.29(s,1H),11.00(s,1H),7.89(s,1H),7.79(dd,J＝17.8,7.8Hz,2H),7.17–7.08(m,3H),6.83(d,J＝6.7Hz,2H),6.60(dd,J＝20.5,8.5Hz,4H),6.48(dd,J＝8.2,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.44(q,J＝17.6Hz,4H),4.16(d,J＝4.7Hz,1H),3.62(d,J＝11.8Hz,2H),3.36–3.27(m,3H),3.13–2.88(m,7H),2.61(d,J＝16.7Hz,1H),2.45–2.35(m,1H),2.11–1.96(m,2H),1.70(d,J＝7.0Hz,1H).LCMS(ESI)C 40 H 41 N 4 O 4 + [M+H] + calculated 641.30, measured 641.30.
Example 327: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 93 was reacted with 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03950) (white solid, 57mg, yield 62%): 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.66(s,1H),9.12(s,1H),7.87(t,J＝6.9Hz,1H),7.71(d,J＝7.7Hz,1H),7.20–7.07(m,3H),6.83(d,J＝6.5Hz,2H),6.66–6.54(m,4H),6.48(dd,J＝8.3,2.5Hz,1H),6.25(d,J＝8.6Hz,2H),5.15(dd,J＝13.2,5.2Hz,1H),4.60(d,J＝17.7Hz,1H),4.49–4.39(m,1H),4.16(d,J＝4.8Hz,1H),3.71–3.60(m,2H),3.33–3.12(m,4H),3.06–2.85(m,6H),2.70–2.58(m,2H),2.17–1.94(m,3H),1.77–1.65(m,1H).LCMS(ESI)m/z:C 40 H 39 FN 4 O 4 + [M+H] + calculated 658.30; found 658.3.
Another target compound (GT-03851) (white solid, 66.00mg, yield 77.05%): 1 H NMR(400MHz,DMSO)δ11.22(s,1H),11.02(s,1H),7.95(t,J＝6.9Hz,1H),7.69(d,J＝7.7Hz,1H),7.19–7.05(m,3H),6.83(d,J＝6.7Hz,2H),6.60(dd,J＝18.2,8.5Hz,4H),6.48(dd,J＝8.2,2.5Hz,1H),6.25(d,J＝8.6Hz,2H),5.15(dd,J＝13.2,5.1Hz,1H),4.63–4.41(m,4H),4.16(d,J＝4.8Hz,1H),3.63(d,J＝13.7Hz,2H),3.32–3.27(m,1H),3.18(s,2H),3.06–2.86(m,5H),2.61(dd,J＝16.5,1.7Hz,1H),2.47–2.38(m,1H),2.12–1.97(m,2H),1.70(dd,J＝11.0,4.5Hz,1H).LCMS(ESI)C 40 H 40 FN 4 O 4 + [M+H] + calculated 659.30, measured 659.30.
Example 328: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 93 was reacted with 3- (6-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione, respectively, to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03951) (white solid, 53mg, yield 57%): 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.72(s,1H),9.12(s,1H),7.97(d,J＝5.3Hz,1H),7.69(d,J＝8.3Hz,1H),7.18–7.08(m,3H),6.83(d,J＝6.6Hz,2H),6.66–6.56(m,4H),6.48(dd,J＝8.3,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.49–4.33(m,2H),4.16(d,J＝4.9Hz,1H),3.71–3.58(m,2H),3.35–3.13(m,4H),3.04–2.85(m,5H),2.66–2.55(m,2H),2.44–2.35(m,1H),2.14–1.97(m,2H),1.77–1.65(m,1H).LCMS(ESI)m/z:C 40 H 39 FN 4 O 4 + [M+H] + calculated 658.30; found 658.3.
Another target compound (GT-03852) (white solid, 67.00mg, yield 78.22%): 1 H NMR(400MHz,DMSO)δ11.26(s,1H),11.02(s,1H),8.05(d,J＝6.0Hz,1H),7.67(d,J＝8.5Hz,1H),7.20–7.07(m,3H),6.83(d,J＝6.7Hz,2H),6.60(dd,J＝19.6,8.5Hz,4H),6.48(dd,J＝8.2,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.14(dd,J＝13.2,5.0Hz,1H),4.43(dd,J＝49.3,17.0Hz,4H),4.16(d,J＝4.8Hz,1H),3.63(d,J＝11.0Hz,2H),3.30(dd,J＝13.4,4.0Hz,3H),3.18(s,2H),3.06–2.85(m,5H),2.61(d,J＝16.9Hz,1H),2.46–2.34(m,1H),2.12–1.94(m,2H),1.70(dd,J＝11.4,4.0Hz,1H).LCMS(ESI)C 40 H 40 FN 4 O 4 + [M+H] + calculated 659.30, measured 659.30.
Example 329: preparation of the following Compounds
Referring to the procedure of scheme 11, one of the intermediates prepared in intermediate example 93 was reacted with 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
two aboveOne of the title compounds (GT-03952) (white solid, 46mg, yield 50%): 1 H NMR(400MHz,DMSO)δ11.02(s,1H),10.90(s,1H),9.13(s,1H),7.68–7.53(m,2H),7.19–7.07(m,3H),6.84(d,J＝6.8Hz,2H),6.65–6.55(m,4H),6.48(dd,J＝8.3,2.4Hz,1H),6.25(d,J＝8.4Hz,2H),5.11(dd,J＝13.3,5.0Hz,1H),4.53(d,J＝18.2Hz,1H),4.40(d,J＝18.1Hz,1H),4.16(d,J＝4.7Hz,1H),3.71–3.58(m,2H),3.36–3.26(m,2H),3.18–3.05(m,2H),3.04–2.85(m,5H),2.65–2.58(m,1H),2.44–2.34(m,1H),2.17–1.97(m,2H),1.76–1.68(m,1H).LCMS(ESI)m/z:C 40 H 39 FN 4 O 4 + [M+H] + calculated 658.30; found 658.3.
Another target compound (GT-03853) (white solid, 65.00mg, yield 75.88%): 1 H NMR(400MHz,DMSO)δ11.42(s,1H),11.01(s,1H),7.77–7.61(m,2H),7.20–7.05(m,3H),6.84(d,J＝6.8Hz,2H),6.60(dd,J＝19.3,8.5Hz,4H),6.48(dd,J＝8.3,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.10(dd,J＝13.2,5.1Hz,1H),4.56–4.35(m,4H),4.16(d,J＝4.8Hz,1H),3.62(d,J＝11.3Hz,2H),3.36–3.24(m,3H),3.15–3.00(m,4H),2.98–2.83(m,3H),2.60(d,J＝16.5Hz,1H),2.43–2.33(m,1H),2.12–1.95(m,2H),1.71(dd,J＝11.4,4.6Hz,1H).LCMS(ESI)C 40 H 40 FN 4 O 4 + [M+H] + calculated 659.30, measured 659.30.
Example 330: preparation of the following Compounds
Referring to scheme 11, step 2 and the procedure of example 1, one of the intermediates prepared in intermediate example 93 was reacted with 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5), respectively, to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03955) (white solid, 16mg, 17% yield): 1 H NMR(400MHz,DMSO)δ11.15(s,1H),11.11(s,1H),9.12(s,1H),8.18(s,1H),8.05(s,2H),7.18–7.07(m,3H),6.84(d,J＝6.6Hz,2H),6.65–6.54(m,4H),6.48(dd,J＝8.3,2.6Hz,1H),6.25(d,J＝8.5Hz,2H),5.18(dd,J＝12.7,5.4Hz,1H),4.58(s,2H),4.16(d,J＝4.9Hz,1H),3.73–3.59(m,2H),3.35–3.26(m,3H),3.20–3.07(m,2H),3.02–2.82(m,6H),2.65–2.53(m,2H),2.13–2.00(m,2H),1.76–1.67(m,1H).LCMS(ESI)m/z:C 40 H 39 N 4 O 5 + [M+H] + calculated 655.29; found 655.3.
Another target compound (GT-03855) (white solid, 54.00mg, yield 63.42%): 1 H NMR(400MHz,DMSO)δ11.48(s,1H),11.14(s,1H),8.26(s,1H),8.14(d,J＝7.8Hz,1H),8.02(d,J＝7.6Hz,1H),7.21–7.04(m,3H),6.83(d,J＝6.8Hz,2H),6.60(dd,J＝18.3,8.5Hz,4H),6.48(dd,J＝8.2,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.18(dd,J＝12.8,5.4Hz,1H),4.56(s,2H),4.16(d,J＝4.9Hz,1H),3.63(d,J＝11.8Hz,2H),3.31(ddd,J＝14.8,10.4,7.8Hz,3H),3.14–2.83(m,7H),2.61(d,J＝15.3Hz,1H),2.14–2.01(m,2H),1.71(dd,J＝11.6,4.9Hz,1H).LCMS(ESI)C 40 H 39 N 4 O 5 + [M+H] + calculated 655.28, measured 655.30.
Example 331: preparation of the following Compounds
Referring to scheme 11, step 2 and example 1, one of the intermediates prepared in intermediate example 93 was reacted with 3- (4- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione to give the corresponding target compound.
The structure characterization data of the prepared target compound are respectively as follows:
one of the two target compounds above (GT-03956) (white solid, 51mg, yield 57%): 1 H NMR(400MHz,DMSO)δ11.05(s,1H),10.61(s,1H),9.12(s,1H),7.92(d,J＝6.9Hz,1H),7.84(d,J＝7.6Hz,1H),7.65(t,J＝7.5Hz,1H),7.19–7.06(m,3H),6.83(d,J＝6.4Hz,2H),6.65–6.56(m,4H),6.48(dd,J＝8.3,2.5Hz,1H),6.25(d,J＝8.5Hz,2H),5.18(dd,J＝13.2,5.1Hz,1H),4.77(d,J＝17.2Hz,1H),4.51(d,J＝17.4Hz,1H),4.46–4.36(m,2H),4.16(d,J＝4.7Hz,1H),3.74–3.60(m,2H),3.35–3.17(m,4H),3.02–2.87(m,5H),2.68–2.62(m,1H),2.36–2.26(m,1H),2.15–2.01(m,2H),1.76–1.67(m,1H).LCMS(ESI)m/z:C 40 H 41 N 4 O 4 + [M+H] + calculated 641.31; found 641.3.
Another target compound (GT-03854) (white solid, 62.00mg, yield 74.41%): 1 H NMR(400MHz,DMSO)δ11.26(s,1H),11.05(s,1H),8.00(d,J＝7.6Hz,1H),7.83(d,J＝7.5Hz,1H),7.63(t,J＝7.6Hz,1H),7.19–7.05(m,3H),6.83(d,J＝6.7Hz,2H),6.66–6.54(m,4H),6.48(dd,J＝8.3,2.4Hz,1H),6.25(d,J＝8.6Hz,2H),5.18(dd,J＝13.2,5.1Hz,1H),4.87(d,J＝17.5Hz,1H),4.52(d,J＝17.6Hz,1H),4.41(s,2H),4.16(d,J＝4.8Hz,1H),3.63(d,J＝11.8Hz,2H),3.38–3.27(m,3H),3.24–3.15(m,2H),3.13–3.04(m,2H),3.01–2.86(m,3H),2.64(d,J＝17.1Hz,1H),2.38–2.27(m,1H),2.13–1.96(m,2H),1.71(dd,J＝11.4,4.6Hz,1H).LCMS(ESI)C 40 H 41 N 4 O 4 + [M+H] + calculated 641.30, measured 641.30.
Example 332:3- (4-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]))]Imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione GT-03592) Is prepared from
The procedure described in scheme 11 was followed using 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]]Imidazol-6-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1231930-57-6) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) gave the title compound (GT-03592) (white solid, 55mg, yield 63.7%). 1 H NMR(400MHz,MeOD)δ8.81(d,J＝3.2Hz,1H),8.50(s,1H),8.42–8.30(m,2H),8.10(d,J＝11.0Hz,1H),7.77–7.69(m,1H),7.65(d,J＝7.7Hz,1H),7.55(d,J＝9.0Hz,1H),5.06(dt,J＝14.2,6.1Hz,2H),4.66–4.32(m,4H),3.95(s,2H),3.36(s,4H),3.19–2.84(m,7H),2.84–2.75(m,1H),2.69(d,J＝15.7Hz,1H),2.50–2.36(m,1H),2.15–2.04(m,1H),1.72(d,J＝6.9Hz,6H).LCMS(ESI)C 39 H 40 F 3 N 10 O 3 + [M+H] + Calculated 753.32, measured 753.3.
Example 333:3- (6-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]))]Imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dioneGT-03593) Is prepared from
The title compound (GT-03593) (white solid, 45mg, yield 63.6%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.80(d,J＝3.0Hz,1H),8.48(s,1H),8.40–8.26(m,2H),8.08(d,J＝11.2Hz,1H),7.80(d,J＝6.0Hz,1H),7.55(d,J＝8.6Hz,2H),5.13–5.00(m,2H),4.45(dd,J＝29.9,20.4Hz,4H),3.85(s,2H),3.27(d,J＝19.8Hz,4H),3.12–2.62(m,9H),2.42(tt,J＝13.5,6.8Hz,1H),2.15–2.01(m,1H),1.72(d,J＝6.9Hz,6H).LCMS(ESI)C 39 H 40 F 3 N 10 O 3 + [M+H] + Calculated 753.32, measured 753.3.
Example 334:3- (7-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]))]Imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dioneGT-03594) Is prepared from
The procedure described in scheme 11 was followed using 5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ]]Imidazol-6-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (CAS number: 1231930-57-6) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) to give the title compound (GT-03594) (white solid, 35mg, yield 50.5%). 1 H NMR(400MHz,MeOD)δ8.81(d,J＝2.9Hz,1H),8.50(s,1H),8.40–8.27(m,2H),8.10(d,J＝11.2Hz,1H),7.55(d,J＝8.9Hz,2H),7.37(d,J＝9.8Hz,1H),5.11–5.00(m,2H),4.54–4.42(m,2H),4.34(s,2H),3.93(s,2H),3.33(d,J＝39.0Hz,4H),3.11–2.63(m,9H),2.40(dt,J＝13.3,8.8Hz,1H),2.16–2.00(m,1H),1.72(d,J＝6.9Hz,6H).LCMS(ESI)C 39 H 40 F 3 N 10 O 3 + [M+H] + Calculated 753.32, measured 753.4.
Example 335:3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione ]GT-03491) Is prepared from
Referring to the procedure of scheme 11, the title compound (GT-03491) (white solid, 40mg, yield 49.9%) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (CAS number 2353496-90-7) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446). 1 H NMR(400MHz,MeOD)δ8.41–8.11(m,1H),7.97(s,1H),7.57(dt,J＝33.6,17.8Hz,3H),7.39(d,J＝9.5Hz,1H),7.31(t,J＝7.5Hz,1H),7.21(s,1H),6.71(s,1H),6.57(d,J＝7.2Hz,1H),5.09–5.02(m,1H),4.66–4.59(m,1H),4.48(t,J＝13.0Hz,2H),4.31(s,1H),3.91(d,J＝13.1Hz,2H),3.77(s,3H),3.54(s,1H),2.95–2.78(m,3H),2.70(d,J＝22.0Hz,4H),2.41(dd,J＝13.4,4.4Hz,1H),2.23(d,J＝11.3Hz,2H),2.10(s,1H),2.00(d,J＝9.6Hz,2H),1.79(d,J＝13.6Hz,6H).LCMS(ESI)C 39 H 44 ClFN 8 O 5 P + [M+H] + Calculated 789.28, measured 789.3.
Example 336: preparation of 3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03512)
Referring to the procedure of scheme 11, the title compound (GT-03512) (white solid, 50mg, 62.4% yield) was prepared using (2- ((5-chloro-2- ((2-methoxy-4- (4- (methylamino) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphino-xide (CAS number 2353496-90-7) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445). 1 H NMR(400MHz,MeOD)δ8.19(s,1H),8.05(s,1H),7.79–7.73(m,1H),7.69(d,J＝7.7Hz,1H),7.62(dd,J＝14.0,7.8Hz,1H),7.53(t,J＝7.9Hz,1H),7.45–7.31(m,2H),7.05(s,1H),6.84(d,J＝9.0Hz,1H),5.10(dd,J＝13.3,5.2Hz,1H),4.72–4.65(m,1H),4.56(t,J＝15.3Hz,2H),4.40(s,1H),3.88(d,J＝12.2Hz,2H),3.83(s,3H),3.77(s,1H),3.27(d,J＝31.1Hz,2H),2.88–2.79(m,4H),2.74–2.66(m,1H),2.51–2.42(m,1H),2.32(d,J＝28.8Hz,4H),2.15–2.07(m,1H),1.79(d,J＝13.6Hz,6H).LCMS(ESI)C 39 H 44 ClFN 8 O 5 P + [M+H] + Calculated 789.28, measured 789.3.
Example 337: preparation of 3- (4- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03650)
The title compound (GT-03650) (white solid, 40mg, yield 63.5%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.35(s,1H),8.13(s,1H),7.99(d,J＝7.5Hz,1H),7.92(d,J＝7.5Hz,1H),7.80–7.69(m,2H),7.62(d,J＝7.2Hz,1H),7.45(t,J＝7.1Hz,2H),7.02(s,1H),6.83(d,J＝8.0Hz,1H),5.27(dd,J＝13.3,5.1Hz,1H),4.70(d,J＝17.3Hz,2H),4.39(s,1H),4.02(d,J＝11.7Hz,2H),3.92(s,3H),3.85(s,1H),3.24(s,2H),3.07–2.73(m,6H),2.59(qd,J＝13.3,4.9Hz,1H),2.42(s,2H),2.37–2.22(m,3H),1.91(d,J＝13.6Hz,6H).LCMS(ESI)C 39 H 45 ClN 8 O 5 P + [M+H] + Calculated 771.29, measured 771.3.
Example 338: preparation of 2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-03645)
The title compound (GT-03645) was obtained as a white solid (35 mg, yield 55.6%) according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.02(s,1H),7.88(d,J＝7.5Hz,1H),7.77(dd,J＝22.1,7.4Hz,2H),7.63(dd,J＝14.4,5.7Hz,3H),7.43–7.32(m,1H),7.20(d,J＝8.7Hz,1H),6.89(s,1H),6.78(d,J＝7.6Hz,1H),6.49(s,1H),5.23(dd,J＝13.2,5.2Hz,1H),4.70(t,J＝24.2Hz,2H),4.19(s,2H),3.98(d,J＝12.9Hz,2H),3.88(s,3H),3.64–3.34(m,9H),3.03(d,J＝12.5Hz,2H),2.96–2.78(m,5H),2.57(dd,J＝13.0,4.5Hz,1H),2.32(d,J＝11.7Hz,2H),2.24(d,J＝5.4Hz,1H),2.00(d,J＝9.6Hz,2H).LCMS(ESI)C 44 H 49 F 3 N 9 O 5 + [M+H] + Calculated 840.38, measured 840.4.
Example 339: n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide [ (ii)GT-03677) Is prepared from
Referring to scheme 11, step 2 and the procedure of example 1, N-methyl-N- (3- (((2- ((4- (4- (methylamino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) methanesulfonamide (GT-M-153) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) prepared as intermediate example 32 gave the title compound (GT-03677) (white solid, 16mg, 26.3% yield). 1 H NMR(400MHz,MeOD)δ8.11(s,1H),7.84(d,J＝7.8Hz,1H),7.76(s,1H),7.65(d,J＝7.7Hz,1H),7.23(ddd,J＝42.0,23.6,8.3Hz,8H),5.09(dd,J＝13.3,5.1Hz,1H),4.61(s,2H),4.48(t,J＝12.7Hz,2H),4.35(s,1H),3.85(d,J＝11.6Hz,2H),3.58(s,1H),3.27(s,1H),3.16(s,3H),3.03(s,2H),2.86–2.67(m,8H),2.43(dt,J＝12.7,8.3Hz,1H),2.28(d,J＝12.0Hz,2H),2.18–2.03(m,3H).LCMS(ESI)C 40 H 45 F 3 N 9 O 5 S + [M+H] + Calculated 820.32, measured 820.3.
Example 340: n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide [GT-03678) Is prepared from
The title compound (GT-03678) (white solid, 25mg, yield 42.2%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.11(s,1H),7.79(d,J＝7.8Hz,1H),7.71(s,1H),7.61(d,J＝8.1Hz,1H),7.34–7.08(m,8H),5.08(dd,J＝13.2,5.2Hz,1H),4.62(s,2H),4.46(q,J＝17.5Hz,2H),4.25(s,2H),3.81(d,J＝12.3Hz,2H),3.31(d,J＝59.8Hz,9H),3.16(s,3H),3.08(s,2H),2.86–2.66(m,5H),2.49–2.35(m,1H),2.21(d,J＝12.1Hz,2H),2.14–2.05(m,1H),1.96(d,J＝10.7Hz,2H).LCMS(ESI)C 43 H 50 F 3 N 10 O 5 S + [M+H] + Calculated 875.36, measured 875.4.
Example 341: n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide @GT-03672) Is prepared from
Referring to scheme 11, step 2 and the procedure of example 1, N-methyl-N- (3- (((2- ((4- (piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) methanesulfonamide (GT-M-151) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) prepared as intermediate example 30 was used to give the title compound (GT-03672) (white solid, 30mg, yield 48.8%). 1 H NMR(400MHz,MeOD)δ8.50(d,J＝2.5Hz,1H),8.45(d,J＝2.4Hz,1H),8.16(s,1H),7.88–7.75(m,2H),7.67(d,J＝7.9Hz,1H),7.22(d,J＝8.8Hz,2H),6.94(s,2H),5.09(dd,J＝13.3,5.1Hz,1H),5.01(s,2H),4.57–4.42(m,4H),3.79(d,J＝13.0Hz,2H),3.51(dd,J＝14.0,6.9Hz,2H),3.33–3.23(m,2H),3.05(d,J＝32.0Hz,8H),2.87–2.75(m,1H),2.75–2.62(m,1H),2.43(qd,J＝13.1,4.6Hz,1H),2.17–2.03(m,1H).LCMS(ESI)C 36 H 39 F 3 N 11 O 5 S + [M+H] + Calculated 794.28, measured 794.3.
Example 342: preparation of 2- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04137)
The title compound (GT-04137) (white solid, 12mg, yield 27.08%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ7.94(s,1H),7.84(d,J＝7.9Hz,1H),7.78(s,1H),7.64(dd,J＝12.3,7.8Hz,2H),7.49(d,J＝3.8Hz,2H),7.32–7.22(m,1H),7.04(s,1H),6.77(s,1H),6.40(s,1H),5.08(dt,J＝11.6,5.8Hz,1H),4.59–4.40(m,5H),3.62(d,J＝9.2Hz,5H),3.22(s,4H),3.17(s,4H),2.94–2.81(m,1H),2.79(s,3H),2.70(dd,J＝15.3,2.4Hz,1H),2.50–2.36(m,3H),2.26–2.05(m,6H),1.15(d,J＝6.0Hz,6H).LCMS(ESI)C 47 H 55 F 3 N 9 O 5 + [M+H] + Calculated 882.43, measured 882.4.
Example 343: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04090)
The title compound (GT-04090) (yellow solid, 30mg, yield 38.7%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,MeOD)δ7.94(s,1H),7.84(d,J＝7.8Hz,1H),7.76(s,1H),7.69–7.57(m,2H),7.53–7.41(m,2H),7.30–7.18(m,1H),7.02(s,1H),6.71(s,1H),6.42(s,1H),5.14–5.04(m,1H),4.73–4.59(m,1H),4.58–4.41(m,3H),4.38(d,J＝47.0Hz,1H),3.52–3.37(m,1H),3.20(s,2H),2.88–2.63(m,10H),2.43(qd,J＝13.2,4.6Hz,1H),2.25–1.95(m,8H),1.14(d,J＝6.0Hz,6H).LCMS(ESI)C 44 H 50 F 3 N 8 O 5 + [M+H] + Calculated 827.39, measured 827.4.
Example 344: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04091)
The title compound (GT-04091) (yellow solid, 30mg, yield 37.9%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ7.95(s,1H),7.78–7.66(m,2H),7.66–7.58(m,1H),7.51–7.41(m,2H),7.28–7.21(m,1H),7.02(s,1H),6.72(s,1H),6.43(s,1H),5.17–5.03(m,1H),4.72–4.65(m,1H),4.64–4.48(m,3H),4.46–4.23(m,1H),3.50(t,J＝12.1Hz,1H),3.23(d,J＝6.2Hz,2H),2.91–2.66(m,10H),2.44(qd,J＝13.2,4.9Hz,1H),2.30–1.95(m,8H),1.15(d,J＝6.0Hz,6H).LCMS(ESI)C 44 H 49 F 4 N 8 O 5 + [M+H] + Calculated 845.38, measured 845.4.
Example 345: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04092)
The title compound (GT-04092) (yellow solid, 30mg, yield 37.9%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ7.95(s,1H),7.83(d,J＝6.1Hz,1H),7.61(dd,J＝8.5,7.0Hz,2H),7.53–7.40(m,2H),7.27–7.18(m,1H),7.03(s,1H),6.71(d,J＝7.8Hz,1H),6.43(s,1H),5.13–5.03(m,1H),4.71–4.23(m,5H),3.50(t,J＝12.2Hz,1H),3.23(d,J＝6.1Hz,2H),2.83–2.65(m,10H),2.43(qd,J＝13.2,4.7Hz,1H),2.28–1.97(m,8H),1.19–1.09(m,6H).LCMS(ESI)C 44 H 49 F 4 N 8 O 5 + [M+H] + Calculated 845.38, measured 845.4.
Example 346: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04093)
The title compound (GT-04093) (yellow solid, 30mg, yield 37.9%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ7.94(s,1H),7.61(dd,J＝9.4,8.3Hz,2H),7.52–7.45(m,2H),7.41(d,J＝9.7Hz,1H),7.28–7.19(m,1H),7.02(s,1H),6.71(s,1H),6.42(s,1H),5.06(dd,J＝13.3,5.2Hz,1H),4.61(s,1H),4.57–4.44(m,3H),4.28(d,J＝44.9Hz,1H),3.46(t,J＝12.1Hz,1H),3.20(d,J＝4.7Hz,2H),2.88–2.66(m,10H),2.41(qd,J＝13.2,4.6Hz,1H),2.25–1.95(m,8H),1.14(d,J＝6.0Hz,6H).LCMS(ESI)C 44 H 49 F 4 N 8 O 5 + [M+H] + Calculated 845.38, measured 845.4.
Example 347: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04097)
The title compound (GT-04097) (yellow solid, 30mg, yield 38.7%) was obtained by referring to scheme 11, step 2 and the method of example 1. 1 H NMR(400MHz,MeOD)δ7.94(s,1H),7.88(d,J＝7.6Hz,1H),7.79(d,J＝7.7Hz,1H),7.63(dt,J＝7.5,3.7Hz,2H),7.49(d,J＝3.8Hz,2H),7.33–7.22(m,1H),7.00(s,1H),6.72(d,J＝9.0Hz,1H),6.40(s,1H),5.20–5.09(m,1H),4.65–4.49(m,4H),4.25(s,1H),3.54(s,1H),3.24(s,1H),2.97–2.61(m,11H),2.47(dt,J＝13.2,11.0Hz,1H),2.29–2.00(m,8H),1.14(d,J＝6.0Hz,6H).LCMS(ESI)C 44 H 50 F 3 N 8 O 5 + [M+H] + Calculated 827.39, measured 827.4.
Example 348: preparation of 2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide (GT-04096)
The title compound (GT-04096) (yellow solid, 30mg, yield 38.1%) was prepared according to the procedure of step 2 of scheme 11 and example 1. 1 H NMR(400MHz,MeOD)δ8.05(s,1H),8.01–7.87(m,3H),7.61(d,J＝8.1Hz,1H),7.51–7.38(m,2H),7.23(dd,J＝11.2,5.0Hz,1H),7.03(s,1H),6.70(s,1H),6.41(s,1H),5.10(dd,J＝12.7,5.4Hz,1H),4.60–4.28(m,4H),3.46(s,1H),2.88–2.54(m,12H),2.19(d,J＝18.8Hz,5H),2.12–1.94(m,3H),1.14(d,J＝6.0Hz,6H).LCMS(ESI)C 44 H 48 F 3 N 8 O 6 + [M+H] + Calculated 841.36, measured 841.4.
Example 349: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04120)
Referring to scheme 11, step 2 and the procedure of example 1, the intermediate example 72 was used to prepare a mixture of (4- (4- ((3- (difluoromethyl) -1-)Piperidin-4-yl) -1H-pyrazol-4-yl-carbamoyl) oxazol-2-yl) (2, 2-trifluoroethyl) carbamic acid tert-butyl ester (GT-D-126) and 3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03234) gave the title compound (GT-04120) (white solid, 25mg, yield 37.0%). 1 H NMR(400MHz,MeOD)δ8.72(s,1H),8.33(s,1H),8.20(d,J＝6.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.82(s,1H),7.75(d,J＝8.0Hz,1H),7.47(s,1H),7.42(d,J＝4.5Hz,1H),6.89(d,J＝54.0Hz,1H),5.22(dd,J＝13.4,5.2Hz,1H),4.65–4.52(m,5H),4.32–4.21(m,2H),3.71(s,2H),3.50(s,1H),3.06(d,J＝7.7Hz,1H),2.94(s,1H),2.84(s,1H),2.54(d,J＝17.4Hz,1H),2.42(s,4H),2.23(s,1H).LCMS(ESI)C 34 H 33 F 5 N 9 O 5 + [M+H] + Calculated 742.25, observed 742.3.
Example 350: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04098)
Referring to the procedure of scheme 11, the (4- (4- ((3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) carbamoyl) oxazol-2-yl) pyridin-2-yl) (2, 2-trifluoroethyl) carbamic acid tert-butyl ester (GT-D-126) and 3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03445) prepared as intermediate example 72 gave the title compound (GT-04098) (white solid, 25mg, 26.2% yield). 1 H NMR(400MHz,MeOD)δ8.83(s,1H),8.36(s,1H),8.23(d,J＝6.3Hz,1H),7.94–7.80(m,2H),7.72(s,1H),7.60(d,J＝6.3Hz,1H),6.99(t,J＝54.4Hz,1H),5.25(dd,J＝13.4,5.2Hz,1H),4.80–4.59(m,5H),4.37(q,J＝8.9Hz,2H),3.76(t,J＝42.7Hz,2H),3.41(d,J＝29.0Hz,2H),2.98(ddd,J＝18.5,13.4,5.3Hz,1H),2.91–2.82(m,1H),2.70–2.36(m,5H),2.31–2.20(m,1H).LCMS(ESI)C 34 H 32 F 6 N 9 O 5 + [M+H] + Calculated 760.24, measured 760.3.
Example 351: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-0419)
The title compound (GT-0419) was prepared according to the method of scheme 11 (white solid, 25mg, yield 26.2%). 1 H NMR(400MHz,MeOD)δ8.98(s,1H),8.51(s,1H),8.37(d,J＝6.3Hz,1H),8.13(d,J＝6.1Hz,1H),7.90(d,J＝12.3Hz,2H),7.76(d,J＝6.1Hz,1H),7.14(t,J＝54.3Hz,1H),5.39(dd,J＝13.2,5.2Hz,1H),4.94–4.65(m,5H),4.52(q,J＝9.0Hz,2H),3.91(t,J＝40.4Hz,2H),3.58(d,J＝34.7Hz,2H),3.20–3.05(m,1H),3.00(d,J＝15.7Hz,1H),2.85–2.52(m,5H),2.41(d,J＝13.1Hz,1H).LCMS(ESI)C 34 H 32 F 6 N 9 O 5 + [M+H] + Calculated 760.24, measured 760.3.
Example 352: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04099)
Referring to the procedure of scheme 11, the (4- (4- ((3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) carbamoyl) oxazol-2-yl) pyridin-2-yl) (2, 2-trifluoroethyl) carbamic acid tert-butyl ester (GT-D-126) and 3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-03446) prepared as intermediate example 72 gave the title compound (GT-04099) (white solid, 25mg, yield 26.2%). 1 H NMR(400MHz,MeOD)δ8.75(s,1H),8.33(s,1H),8.19(d,J＝6.0Hz,1H),7.66(s,1H),7.57(s,1H),7.54–7.44(m,2H),6.95(t,J＝54.6Hz,1H),5.17(dd,J＝13.3,5.2Hz,1H),4.61(dd,J＝26.9,18.4Hz,5H),4.29(q,J＝9.1Hz,2H),3.67(t,J＝38.8Hz,2H),3.42(d,J＝64.8Hz,2H),2.94(ddd,J＝18.5,13.4,5.3Hz,1H),2.87–2.77(m,1H),2.63–2.36(m,5H),2.28–2.16(m,1H).LCMS(ESI)C 34 H 32 F 6 N 9 O 5 + [M+H] + Calculated 760.24, measured 760.3.
Example 353: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04089)
The title compound (GT-04089) (white solid, 25mg, yield 37.0%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.61(s,1H),8.21(s,1H),8.08(d,J＝5.9Hz,1H),7.86(t,J＝7.5Hz,1H),7.82–7.75(m,1H),7.62(t,J＝7.6Hz,1H),7.40(s,1H),7.33(d,J＝5.9Hz,1H),6.83(t,J＝54.3Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.64(dd,J＝42.9,17.4Hz,3H),4.43(s,2H),4.16(q,J＝9.2Hz,2H),3.56(d,J＝70.4Hz,2H),3.37(dd,J＝13.4,11.8Hz,2H),2.94–2.79(m,1H),2.72(d,J＝15.7Hz,1H),2.53–2.22(m,5H),2.19–2.08(m,1H).LCMS(ESI)C 34 H 33 F 5 N 9 O 5 + [M+H] + Calculated 742.25, observed 742.3.
Example 354: preparation of N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide (GT-04088)
Referring to the procedure of scheme 11, the (4- (4- ((3- (difluoromethyl) -1- (piperidin-4-yl) -1H-pyrazol-4-yl) carbamoyl) oxazol-2-yl) pyridin-2-yl) (2, 2-trifluoroethyl) carbamic acid tert-butyl ester (GT-D-126) and 5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (CAS number: 1312023-72-5) were prepared to give the title compound (GT-04088) (white solid, 25mg, 36.4%) in yield. 1 H NMR(400MHz,MeOD)δ8.60(s,1H),8.21(s,1H),8.09(d,J＝5.8Hz,1H),8.03(s,1H),7.95(s,2H),7.36(s,1H),7.30(d,J＝5.8Hz,1H),6.84(t,J＝54.8Hz,1H),5.10(dd,J＝12.6,5.5Hz,1H),4.51(s,3H),4.14(q,J＝9.2Hz,2H),3.56(t,J＝38.6Hz,2H),3.39–3.22(m,2H),2.80(ddd,J＝17.8,14.4,5.1Hz,1H),2.67(ddd,J＝13.4,7.8,4.6Hz,2H),2.31(s,4H),2.11–2.03(m,1H).LCMS(ESI)C 34 H 31 F 5 N 9 O 6 + [M+H] + Calculated 756.23, measured 756.2.
Example 355: preparation of N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide (GT-03383)
Referring to the procedure of scheme 56, 4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] prepared in intermediate example 78 was used ]Preparation of furan-2-carboxylic acid (GT-D-200) and 3- (5- (aminomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (CAS number: 1010100-28-3) the title compound (GT-03383) gave the title compound (GT-03383) (grey solid, 32mg, yield 51.9%). 1 H NMR(400MHz,DMSO)δ10.97(s,1H),9.62(t,J＝6.1Hz,1H),8.20–8.06(m,2H),7.99–7.86(m,2H),7.78–7.66(m,2H),7.58(s,1H),7.51(t,J＝8.6Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.62(d,J＝6.0Hz,2H),4.39(dd,J＝54.6,17.4Hz,2H),2.97–2.85(m,1H),2.63(t,J＝18.2Hz,1H),2.44–2.33(m,1H),2.07–1.95(m,1H).LCMS(ESI)C 27 H 20 N 3 O 7 + [M+H] + Calculated 498.13, measured 498.1.
Example 356: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide (GT-03522)
The title compound (GT-03522) (yellow solid, 53mg, yield 62.52%) was prepared according to the method of scheme 59. 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.61–8.58(m,1H),7.85(d,J＝8.7Hz,2H),7.67(d,J＝7.7Hz,1H),7.45(d,J＝10.6Hz,2H),7.37(t,J＝6.0Hz,2H),7.13(d,J＝6.5Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.50–4.44(m,3H),4.30(d,J＝17.4Hz,1H),3.51–3.43(m,2H),3.17(d,J＝8.1Hz,1H),3.06(t,J＝11.5Hz,3H),2.93–2.88(m,2H),2.68–2.58(m,2H),2.40(dd,J＝13.3,4.4Hz,1H),2.10(d,J＝9.9Hz,4H),2.01–1.86(m,7H),1.72–1.50(m,9H),1.31–1.22(m,3H).LCMS(ESI)C 43 H 50 ClN 8 O 5 + [M+H] + Calculated 793.35, measured 793.30.
Example 357: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylene) azetidin-1-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide (GT-03541)
The title compound (GT-03541) was prepared according to the method of scheme 59 (yellow solid, 44mg, yield 53.95%). 1 H NMR(400MHz,DMSO)δ11.00(s,1H),8.61(d,J＝8.1Hz,1H),7.85(dd,J＝9.2,2.4Hz,2H),7.72(d,J＝7.9Hz,1H),7.44(d,J＝5.2Hz,2H),7.38(d,J＝2.1Hz,1H),7.33(d,J＝7.8Hz,1H),7.13(dd,J＝8.8,2.1Hz,1H),6.62(s,1H),5.33–5.21(m,1H),5.19–5.09(m,2H),5.07–4.98(m,1H),4.84(d,J＝15.9Hz,1H),4.54–4.42(m,4H),4.34(dd,J＝17.4,3.9Hz,1H),3.28(t,J＝5.2Hz,2H),3.03(t,J＝12.1Hz,2H),2.93(dd,J＝22.1,8.8Hz,1H),2.60(d,J＝16.5Hz,1H),2.43–2.31(m,1H),2.07(dd,J＝28.2,7.3Hz,4H),1.90(d,J＝12.3Hz,4H),1.65–1.49(m,4H),1.35–1.16(m,3H).LCMS(ESI)C 41 H 44 ClN 8 O 5 + [M+H] + Calculated 763.30, measured 763.30.
Example 358: preparation of N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((3- ((1S) - (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) (hydroxy) methyl) -3-hydroxyazetidin-1-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide (GT-03581)
The title compound (GT-03581) (yellow solid, 44mg, yield 51.65%) was obtained by the method of scheme 59. 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.60(d,J＝8.2Hz,1H),7.86(dd,J＝9.2,4.5Hz,2H),7.68(dd,J＝8.5,4.6Hz,2H),7.61(t,J＝6.8Hz,1H),7.48(d,J＝9.7Hz,1H),7.38(d,J＝2.2Hz,1H),7.13(dd,J＝8.8,2.2Hz,1H),5.20–5.08(m,2H),4.49(dd,J＝9.9,3.5Hz,4H),4.33(dd,J＝16.4,9.9Hz,3H),4.21(dd,J＝10.5,4.9Hz,1H),4.11–4.04(m,1H),3.92–3.79(m,3H),3.20–3.13(m,2H),3.04(t,J＝12.4Hz,2H),2.96–2.85(m,1H),2.60(d,J＝16.7Hz,1H),2.47–2.26(m,1H),2.06(dd,J＝36.8,8.2Hz,4H),1.88(t,J＝10.6Hz,4H),1.68–1.50(m,4H),1.32–1.22(m,2H).LCMS(ESI)C41H46ClN8O7 + [M+H] + Calculated 797.31, measured 797.30.
Example 359: preparation of N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) piperidine-3-carboxamide (GT-03584)
The title compound (GT-03584) was prepared according to the method of scheme 59 (yellow solid, 36mg, yield 43.44%). 1 H NMR(400MHz,DMSO)δ10.99(s,1H),8.56(s,1H),8.24(d,J＝8.8Hz,1H),8.06(d,J＝8.0Hz,1H),7.90(d,J＝8.7Hz,1H),7.67(dd,J＝7.6,4.3Hz,1H),7.44(s,1H),7.34(dd,J＝17.5,9.6Hz,2H),7.21(d,J＝2.1Hz,1H),7.02–6.99(m,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.45(d,J＝7.4Hz,3H),4.34(d,J＝13.1Hz,2H),4.07(d,J＝9.1Hz,2H),3.52–3.43(m,2H),3.23–3.13(m,3H),2.95–2.79(m,4H),2.64(dd,J＝28.3,11.0Hz,2H),2.44–2.34(m,1H),2.22(dd,J＝11.4,6.8Hz,1H),1.98(dd,J＝14.1,9.9Hz,4H),1.77(dt,J＝46.5,15.2Hz,4H),1.23(s,8H),1.12(s,6H).LCMS(ESI)C 46 H 55 ClN 7 O 5 + [M+H] + Calculated 820.39, measured 820.40.
Example 360: preparation of N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylene) azetidin-1-yl) methyl) piperidin-1-yl) piperidine-3-carboxamide (GT-03586)
The title compound (GT-03586) (yellow solid, 47mg, yield 58.88%) was obtained by the method of scheme 59. 1 H NMR(400MHz,DMSO)δ11.50(s,1H),11.00(s,1H),8.59(d,J＝1.6Hz,1H),8.18(d,J＝8.4Hz,1H),7.93(dd,J＝20.9,8.0Hz,2H),7.73(d,J＝7.9Hz,1H),7.44(s,1H),7.33(d,J＝7.7Hz,1H),7.21(d,J＝2.2Hz,2H),7.01(dd,J＝8.8,2.1Hz,1H),6.63(s,1H),5.27(d,J＝15.1Hz,1H),5.22–5.08(m,2H),5.03(d,J＝14.6Hz,1H),4.84(d,J＝14.7Hz,1H),4.52–4.41(m,3H),4.34(dd,J＝16.2,5.0Hz,2H),4.07(d,J＝9.1Hz,1H),3.27(d,J＝5.6Hz,2H),3.10(t,J＝11.8Hz,2H),2.96–2.87(m,1H),2.60(d,J＝16.5Hz,1H),2.46–2.34(m,1H),2.00(ddd,J＝34.8,23.3,8.8Hz,4H),1.33–1.20(m,8H),1.13(s,6H).LCMS(ESI)C 44 H 49 ClN 7 O 5 + [M+H] + Calculated 790.34, measured 790.30.
Example 361: preparation of 7-cyclopentyl-2- ((5- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (GT-03663)
The title compound (GT-03663) (yellow solid, 36mg, yield 42.23%) was prepared according to the method of scheme 59. 1 H NMR(400MHz,DMSO)δ11.64(s,1H),10.99(s,1H),10.52(s,1H),9.02(s,1H),8.21(dd,J＝9.4,2.4Hz,1H),8.08(s,1H),7.66(dd,J＝8.5,5.4Hz,2H),7.50–7.41(m,1H),7.36(dd,J＝14.7,7.9Hz,1H),6.84(s,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.80(s,1H),4.43(d,J＝11.3Hz,2H),4.32(s,2H),3.72–3.63(m,3H),3.57–3.37(m,3H),3.05(s,7H),2.91(dd,J＝10.9,6.6Hz,3H),2.67(d,J＝4.2Hz,1H),2.34–2.24(m,3H),2.17–1.91(m,12H),1.85–1.77(m,2H),1.64(d,J＝5.9Hz,2H),1.49–1.41(m,2H).LCMS(ESI)C 44 H 55 N 10 O 4 + [M+H] + Calculated 787.43, measured 787.50.
Example 362: preparation of 7-cyclopentyl-2- ((5- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) azetidin-1-yl) methyl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (GT-03674)
The title compound (GT-03674) was prepared according to the method of scheme 59 (yellow solid, 10mg, yield 45.84%). 1 H NMR(400MHz,DMSO)δ11.56(s,1H),10.99(s,1H),9.00(s,1H),8.15(dd,J＝9.1,1.9Hz,1H),7.94(s,1H),7.68(dd,J＝7.7,3.3Hz,1H),7.60(d,J＝9.5Hz,1H),7.47(d,J＝12.9Hz,1H),7.38(dd,J＝15.5,8.0Hz,1H),6.83(s,1H),5.11(dd,J＝13.2,4.9Hz,1H),4.84–4.77(m,1H),4.44(d,J＝17.4Hz,1H),4.31(d,J＝17.3Hz,1H),4.12(dd,J＝8.9,5.2Hz,2H),4.06–4.01(m,2H),3.67(d,J＝11.5Hz,3H),3.29(d,J＝8.3Hz,1H),3.16–3.10(m,2H),3.06(s,6H),2.96–2.88(m,1H),2.75(dd,J＝18.0,7.3Hz,2H),2.60(dd,J＝16.0,3.1Hz,1H),2.34(ddd,J＝19.4,12.6,8.5Hz,3H),2.09–1.81(m,9H),1.68–1.61(m,2H),1.35(dd,J＝23.5,12.5Hz,2H).LCMS(ESI)C 42 H 51 N 10 O 4 + [M+H] + Calculated 759.40, measured 759.50.
Example 363: preparation of N- (2-chloro-6-methylphenyl) -2- ((6- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide (GT-03539)
The title compound (GT-03539) was prepared according to the method of scheme 59 (as a pale yellow solid, 10mg, yield 11.86%). 1 H NMR(400MHz,DMSO)δ11.45(s,1H),11.00(s,1H),9.91(s,1H),8.22(s,1H),7.68(d,J＝7.8Hz,1H),7.38–7.35(m,2H),7.34–7.27(m,3H),6.05(s,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.39(dd,J＝42.6,17.3Hz,4H),2.96–2.90(m,6H),2.90–2.80(m,2H),2.45–2.30(m,6H),2.25(s,3H),2.10(s,4H),2.05–2.01(m,1H),1.97–1.87(m,4H),1.57–1.50(m,2H),1.17–1.07(m,2H).LCMS(ESI)C 41 H 47 ClN 9 O 4 S + [M+H] + Calculated 795.3, found 796.2.
Example 364: preparation of 3- (5- ((4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04366)
The title compound (GT-04366) (white solid, 15mg, yield 56.34%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ9.07–8.91(m,1H),7.81(dd,J＝15.7,8.2Hz,2H),7.70(d,J＝16.1Hz,1H),7.63(d,J＝7.9Hz,1H),7.27(dd,J＝18.7,9.9Hz,2H),7.14(s,1H),5.08(dd,J＝13.2,5.0Hz,1H),4.41(dd,J＝33.8,15.7Hz,5H),4.21(s,2H),3.98–3.86(m,2H),3.49(d,J＝14.0Hz,2H),3.36(dd,J＝17.6,12.1Hz,2H),3.03(dd,J＝28.8,16.6Hz,2H),2.78(dt,J＝38.5,14.8Hz,2H),2.43(d,J＝13.0Hz,1H),2.21–1.88(m,9H),1.68(d,J＝12.2Hz,2H).LCMS(ESI)C 45 H 43 F 2 N 8 O 5 + [M+H] + Calculated 813.33, measured 407.3/813.3.
Example 365: preparation of 3- (5- ((4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04387)
The title compound (GT-04387) was prepared according to the method of scheme 11 (white solid, 28mg, 99.94% yield). 1 H NMR(400MHz,MeOD)δ9.22–8.88(m,1H),7.94–7.73(m,2H),7.58(d,J＝8.5Hz,1H),7.42–7.15(m,3H),5.08(dd,J＝13.3,5.0Hz,1H),4.46(dd,J＝26.6,17.6Hz,5H),4.22(s,2H),4.16–3.96(m,1H),3.51(d,J＝10.6Hz,4H),3.43(d,J＝9.4Hz,1H),3.36(t,J＝8.4Hz,1H),3.19–2.96(m,2H),2.88–2.63(m,2H),2.49–2.36(m,1H),2.28–2.01(m,7H),1.91(d,J＝14.3Hz,1H),1.76–1.38(m,2H).LCMS(ESI)C 45 H 42 F 3 N 8 O 5 + [M+H] + Calculated 831.32, found 416.3/831.3.
Example 366: preparation of 3- (4- ((4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04388)
The title compound (GT-04388) was obtained as a white solid (27 mg, 98.33% yield) according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ9.19–8.99(m,1H),7.92–7.73(m,3H),7.60(t,J＝7.6Hz,1H),7.40–7.14(m,3H),5.13(dd,J＝13.2,5.1Hz,1H),4.58(dd,J＝19.3,7.2Hz,1H),4.37(t,J＝19.7Hz,4H),4.22(s,2H),4.05–3.93(m,1H),3.56(d,J＝20.5Hz,2H),3.40(ddd,J＝24.1,14.0,6.3Hz,3H),3.04(s,2H),2.80(dt,J＝42.9,14.6Hz,2H),2.44(s,1H),2.12(ddd,J＝91.2,37.1,28.6Hz,9H),1.74(s,2H).LCMS(ESI)C 45 H 43 F 2 N 8 O 5 + [M+H] + Calculated 813.33, measured 407.3/813.3.
Example 367: preparation of 3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04262)
The title compound (GT-04262) was obtained as a white solid (71 mg, 96.55% yield) according to the method of scheme 11. 1 H NMR(400MHz,DMSO-d 6 )δ11.30(s,1H),11.01(d,J＝6.9Hz,1H),8.79–8.38(m,2H),7.90(s,1H),7.84(d,J＝7.7Hz,1H),7.78(d,J＝7.8Hz,1H),7.47–7.31(m,2H),7.09(d,J＝33.7Hz,3H),6.62(d,J＝6.3Hz,2H),5.45(s,1H),5.20–5.08(m,1H),4.51–4.38(m,5H),4.02(s,1H),3.67(s,2H),3.37(s,4H),3.12(s,2H),2.97–2.89(m,1H),2.62(d,J＝17.1Hz,1H),2.47–2.39(m,1H),2.17–1.81(m,5H).LCMS(ESI)C 39 H 38 F 2 N 9 O 3 + [M+H] + Calculated 718.30, measured 718.40.
Example 368: preparation of 3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04263)
The title compound (GT-04263) was obtained (white solid, 73mg, yield 96.83%) by the method of scheme 11. 1 H NMR(400MHz,DMSO-d 6 )δ11.08–10.82(m,2H),8.58(d,J＝132.9Hz,2H),7.93(t,J＝6.9Hz,1H),7.79–7.59(m,2H),7.35(td,J＝9.6,4.4Hz,2H),7.09(d,J＝31.8Hz,2H),6.62(s,1H),5.45(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.92(s,1H),4.63–4.41(m,6H),4.03(s,1H),3.64(d,J＝38.3Hz,2H),3.30–3.06(m,4H),2.91(dd,J＝12.7,4.6Hz,1H),2.60(s,1H),2.47–2.42(m,1H),2.27–1.58(m,5H).LCMS(ESI)C 39 H 37 F 3 N 9 O 3 + [M+H] + Calculated 736.29, measured 736.30.
Example 369: preparation of 3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04264)
The title compound (GT-04264) was obtained as a white solid (25 mg, 31.73% yield) according to the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.43(d,J＝39.5Hz,2H),7.87(t,J＝62.3Hz,2H),7.63–7.27(m,2H),7.06(d,J＝53.2Hz,2H),6.90–6.06(m,3H),5.40(d,J＝47.3Hz,1H),5.08(dd,J＝13.3,5.1Hz,1H),4.61–4.35(m,4H),4.33–3.24(m,10H),2.91–2.63(m,2H),2.59–2.35(m,2H),2.06(dd,J＝36.9,31.5Hz,4H).LCMS(ESI)C 39 H 37 F 3 N 9 O 3 + [M+H] + Calculated 736.29, measured 736.30.
Example 370: preparation of 3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04265)
The title compound (GT-04265) (white solid, 67mg, yield 88.87%) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.95(d,J＝8.2Hz,1H),10.76(s,1H),8.67(s,1H),8.32(s,1H),7.81–6.81(m,7H),6.53(s,1H),5.05(dd,J＝13.0,5.2Hz,1H),4.59–4.26(m,6H),3.95(s,1H),3.60(s,1H),3.24–2.76(m,8H),2.54(d,J＝18.9Hz,1H),2.33(s,1H),1.99(d,J＝22.9Hz,5H).LCMS(ESI)C 39 H 37 F 3 N 9 O 3 + [M+H] + Calculated 736.29, measured 736.30.
Example 371: preparation of 5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (GT-04266)
The title compound (GT-04266) (white solid, 70mg, yield 93.37%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.46(s,1H),11.15(d,J＝6.8Hz,1H),9.15(s,1H),8.76–8.38(m,1H),7.94(dddd,J＝54.2,46.5,41.5,27.3Hz,5H),7.43–7.28(m,1H),7.09(d,J＝29.8Hz,2H),6.61(d,J＝7.1Hz,1H),5.53–5.10(m,2H),5.00–3.97(m,4H),3.61(ddt,J＝9.2,6.6,4.6Hz,4H),3.25(d,J＝66.7Hz,4H),2.92–2.84(m,1H),2.64–2.54(m,2H),2.34–1.74(m,5H).LCMS(ESI)C 39 H 36 F 2 N 9 O 4 + [M+H] + Calculated 732.28, found 732.30.
Example 372: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04421)
The title compound (GT-04421) (white solid) was obtained by the method described in reference to scheme 1152mg, 67.94% yield). 1 H NMR(400MHz,MeOD)δ8.85(d,J＝17.0Hz,1H),7.92(dd,J＝20.7,10.3Hz,3H),7.80(t,J＝11.2Hz,1H),7.68–7.59(m,3H),7.51(d,J＝3.4Hz,1H),7.24(d,J＝3.8Hz,1H),7.15(d,J＝8.6Hz,2H),5.16(dt,J＝16.1,8.1Hz,1H),4.92(d,J＝17.0Hz,1H),4.59(t,J＝10.2Hz,6H),4.37(dt,J＝19.6,9.8Hz,2H),4.12–3.34(m,8H),3.04(dd,J＝15.9,8.2Hz,1H),2.96–2.77(m,3H),2.77–2.67(m,2H),2.54(dt,J＝13.3,8.6Hz,1H),2.27–2.16(m,1H).LCMS(ESI)C 43 H 41 FN 9 O 5 S + [M+H] + Calculated 814.29, measured 814.3.
Example 373: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04422)
The title compound (GT-04422) (white solid, 52mg, yield 68.73%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.85(s,1H),9.03(s,1H),7.90(s,1H),7.85–7.61(m,6H),7.52(d,J＝3.6Hz,1H),7.30(d,J＝3.6Hz,1H),7.12(d,J＝8.7Hz,2H),6.40(s,1H),5.12(dd,J＝13.1,5.2Hz,1H),4.81(d,J＝17.1Hz,1H),4.54–4.47(m,2H),4.40(d,J＝15.7Hz,2H),4.28(t,J＝7.2Hz,2H),3.97(d,J＝12.8Hz,4H),3.48(s,8H),2.89(dt,J＝22.7,10.1Hz,4H),2.72–2.53(m,5H),2.47–2.36(m,1H),2.21(d,J＝10.7Hz,2H),2.09–2.02(m,1H),1.86(d,J＝9.7Hz,2H).LCMS(ESI)C 48 H 50 FN 10 O 5 S + [M+H] + Calculated 897.37, measured 897.4.
Example 374: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04423)
The title compound (GT-04423) was prepared according to the method of scheme 11 (white solid, 34mg, yield 44.94%). 1 H NMR(400MHz,DMSO)δ10.86(s,1H),9.02(s,1H),7.90(s,1H),7.80(dd,J＝18.5,8.7Hz,4H),7.72(d,J＝8.5Hz,2H),7.52(d,J＝3.5Hz,1H),7.30(d,J＝3.6Hz,1H),7.11(d,J＝8.2Hz,2H),6.40(s,1H),5.12(dd,J＝13.1,5.1Hz,1H),4.82(d,J＝17.0Hz,1H),4.52(d,J＝14.6Hz,2H),4.42(d,J＝17.3Hz,3H),4.26(d,J＝7.1Hz,2H),3.88(d,J＝49.4Hz,4H),3.21(s,8H),3.03(s,2H),2.96–2.88(m,2H),2.67(t,J＝10.6Hz,2H),2.58(dd,J＝13.9,6.8Hz,2H),2.47–2.29(m,5H),2.08–2.02(m,1H).LCMS(ESI)C 48 H 50 FN 10 O 5 S + [M+H] + Calculated 897.37, measured 897.4.
Example 375: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- ((1S, 4S) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide (GT-04424)
The title compound (GT-04424) was prepared according to the method of scheme 11 (42 mg, yield 55.34%) as a white solid. 1 H NMR(400MHz,DMSO)δ11.03(s,1H),10.85(s,1H),8.94(s,1H),8.00(s,1H),7.88(d,J＝7.8Hz,1H),7.82–7.76(m,2H),7.69(dd,J＝33.7,9.5Hz,3H),7.52(d,J＝3.5Hz,1H),7.30(d,J＝3.5Hz,1H),6.78(t,J＝22.3Hz,2H),6.38(s,1H),5.11(dd,J＝13.2,4.9Hz,1H),4.84–4.72(m,2H),4.66(s,1H),4.47(dd,J＝26.7,10.7Hz,5H),4.26(t,J＝7.1Hz,2H),3.85(d,J＝11.0Hz,1H),3.64(d,J＝9.6Hz,1H),3.09–2.84(m,4H),2.71–2.55(m,6H),2.43(s,1H),2.20(d,J＝9.9Hz,1H),2.06(s,1H).LCMS(ESI)C 44 H 41 FN 9 O 5 S + [M+H] + Calculated 826.29, measured 826.3.
Example 376: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04427)
The title compound (GT-04427) (white solid, 46mg, yield 61.61%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.18(s,1H),11.01(d,J＝8.2Hz,1H),9.10(s,1H),7.96(s,1H),7.82(d,J＝5.9Hz,4H),7.73(d,J＝8.7Hz,2H),7.53(d,J＝3.6Hz,1H),7.33(d,J＝3.6Hz,1H),7.18(d,J＝7.7Hz,2H),6.40(s,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.80(d,J＝17.1Hz,1H),4.63(d,J＝12.4Hz,1H),4.51(dd,J＝16.4,6.3Hz,2H),4.33(ddd,J＝27.9,15.9,8.2Hz,5H),3.97(s,2H),3.48(s,2H),2.95–2.84(m,4H),2.66–2.58(m,6H),2.44(dd,J＝13.3,4.7Hz,1H),2.33(s,1H),2.26(s,1H),2.02(d,J＝5.1Hz,3H).LCMS(ESI)C 45 H 45 FN 9 O 5 S + [M+H] + Calculated 842.32, measured 842.3.
Example 377: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04429)
The title compound (GT-04429) (white solid, 42mg, yield 55.73%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.66(s,1H),11.02(s,1H),9.04(s,1H),8.10(s,1H),7.97(d,J＝7.8Hz,1H),7.82(dd,J＝19.0,8.8Hz,3H),7.70(d,J＝8.8Hz,2H),7.53(d,J＝3.6Hz,1H),7.33(d,J＝3.6Hz,1H),6.98(d,J＝8.9Hz,2H),6.39(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.79(d,J＝17.3Hz,1H),4.52(dd,J＝17.1,12.5Hz,2H),4.45–4.37(m,3H),4.25(t,J＝7.1Hz,2H),3.99(s,2H),3.73(d,J＝11.7Hz,2H),3.56–3.49(m,3H),3.01–2.85(m,2H),2.70–2.54(m,4H),2.40(dd,J＝29.9,12.8Hz,3H),2.03(d,J＝8.7Hz,3H).LCMS(ESI)C 45 H 43 FN 9 O 5 S + [M+H] + Calculated 840.31, measured 840.3.
Example 378: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 3-difluoropiperidin-4-yl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04459)
The title compound (GT-04459) was prepared according to the method of scheme 11 (42 mg, yield 58.54%) as a white solid. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.10(s,1H),7.81(dd,J＝13.9,7.6Hz,3H),7.73(d,J＝8.6Hz,3H),7.64(s,1H),7.53(d,J＝3.6Hz,1H),7.33(d,J＝3.6Hz,1H),7.13(d,J＝7.9Hz,2H),6.40(s,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.80(d,J＝17.2Hz,1H),4.51(dd,J＝17.5,6.1Hz,2H),4.38(d,J＝14.1Hz,1H),4.26(t,J＝7.1Hz,2H),4.15(s,3H),3.53(s,6H),3.30(s,6H),2.89(dd,J＝18.1,11.6Hz,2H),2.66–2.54(m,4H),2.45–2.33(m,3H),2.22(s,1H),2.05–1.96(m,1H).LCMS(ESI)C 48 H 48 F 3 N 10 O 5 S + [M+H] + Calculated 933.35, measured 933.4.
Example 379: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide (GT-04460)
The title compound (GT-04460) (white solid, 32mg, yield 42.17%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ11.01(s,1H),10.74(s,1H),9.05(s,1H),7.97(s,1H),7.88–7.75(m,4H),7.66(d,J＝8.6Hz,2H),7.53(d,J＝3.5Hz,1H),7.33(d,J＝3.5Hz,1H),6.74(d,J＝8.5Hz,2H),6.38(s,1H),5.14(dd,J＝13.3,4.9Hz,1H),4.84–4.65(m,3H),4.55–4.43(m,4H),4.37(d,J＝16.8Hz,1H),4.26(t,J＝7.0Hz,2H),3.80–3.53(m,4H),3.25(s,1H),2.97–2.83(m,2H),2.61(dd,J＝28.5,16.4Hz,5H),2.40(dd,J＝31.1,13.4Hz,1H),2.20(d,J＝10.1Hz,1H),2.03(s,1H).LCMS(ESI)C 44 H 41 FN 9 O 5 S + [M+H] + Calculated 826.29, measured 826.3.
Example 380: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04489)
The title compound (GT-04489) was obtained as a white solid (47 mg, yield 57.47%) according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.58(d,J＝8.1Hz,1H),11.02(s,1H),10.63(s,1H),9.11(d,J＝10.0Hz,1H),8.52–8.42(m,1H),8.39(dd,J＝9.9,5.7Hz,1H),8.20(dt,J＝5.5,2.3Hz,1H),7.93(d,J＝11.7Hz,1H),7.88–7.85(m,1H),7.83–7.72(m,1H),6.10(s,1H),5.16(dd,J＝13.3,5.0Hz,1H),4.62–4.31(m,4H),3.47(dd,J＝43.5,10.7Hz,3H),3.15(d,J＝11.9Hz,2H),2.92(dd,J＝21.4,9.3Hz,1H),2.62(d,J＝17.3Hz,1H),2.44(dd,J＝13.2,4.9Hz,1H),2.41–2.09(m,4H),2.08–1.98(m,1H),1.64(d,J＝9.5Hz,6H).LCMS(ESI)C 36 H 36 F 3 N 6 O 5 S + [M+H] + Calculated 721.24, found 721.3.
Example 381: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04505)
The title compound (GT-04505) (white solid, 55mg, yield 65.69%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.58(d,J＝6.9Hz,1H),11.03(d,J＝10.5Hz,1H),10.73(d,J＝65.4Hz,1H),9.11(d,J＝9.8Hz,1H),8.55–8.32(m,2H),8.19(dd,J＝7.8,0.9Hz,1H),7.99–7.87(m,2H),7.72(dd,J＝11.5,7.9Hz,1H),6.11(s,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.66–4.45(m,4H),3.64(d,J＝35.5Hz,2H),3.44(s,1H),3.23(s,2H),2.92(dd,J＝17.5,5.5Hz,1H),2.62(d,J＝15.9Hz,1H),2.48–2.41(m,1H),2.40–2.12(m,4H),2.07–1.98(m,1H),1.64(d,J＝8.3Hz,6H).LCMS(ESI)C 36 H 35 F 4 N 6 O 5 S + [M+H] + Calculated 739.23, measured 739.3.
Example 382: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04506)
The title compound (GT-04506) (white solid, 55mg, yield 65.69%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.58(d,J＝6.7Hz,1H),11.17(s,1H),11.03(d,J＝9.7Hz,1H),9.12(d,J＝10.0Hz,1H),8.49–8.43(m,1H),8.39(dd,J＝10.0,5.6Hz,1H),8.23–8.15(m,1H),8.08(t,J＝7.3Hz,1H),7.94(d,J＝7.3Hz,1H),7.70(t,J＝7.8Hz,1H),6.11(s,1H),5.16(dd,J＝13.3,5.0Hz,1H),4.55–4.37(m,4H),3.58(dd,J＝48.1,36.9Hz,3H),3.24(d,J＝9.7Hz,2H),3.00–2.88(m,1H),2.62(d,J＝17.0Hz,1H),2.47–2.42(m,1H),2.40–2.15(m,4H),2.05(dd,J＝13.6,8.5Hz,1H),1.65(d,J＝8.9Hz,6H).LCMS(ESI)C 36 H 35 F 4 N 6 O 5 S + [M+H] + Calculated 739.23, measured 739.3.
Example 383: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04507)
The title compound (GT-04507) (white solid, 55mg, yield 65.69%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.58(d,J＝6.8Hz,1H),11.02(d,J＝9.6Hz,1H),10.92(s,1H),9.12(d,J＝9.0Hz,1H),8.47(dd,J＝7.4,4.0Hz,1H),8.42–8.34(m,1H),8.20(dt,J＝5.2,2.1Hz,1H),7.94(d,J＝10.2Hz,1H),7.67(dd,J＝19.3,9.4Hz,2H),6.11(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.58–4.39(m,4H),3.75–3.49(m,2H),3.42(d,J＝10.8Hz,1H),3.14(d,J＝11.7Hz,2H),2.99–2.86(m,1H),2.61(d,J＝15.1Hz,1H),2.44–2.40(m,1H),2.37–2.09(m,4H),2.05–1.97(m,1H),1.64(d,J＝8.4Hz,6H).LCMS(ESI)C 36 H 35 F 4 N 6 O 5 S + [M+H] + Calculated 739.23, measured 739.3.
Example 384: preparation of 2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3, 3-difluoropiperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide (GT-04514)
The title compound (GT-04514) was prepared according to the method of scheme 11 (white solid, 53mg, yield 71.20%). 1 H NMR(400MHz,DMSO)δ11.14(s,1H),11.01(s,1H),9.07(s,1H),7.89(s,1H),7.79(q,J＝8.1Hz,4H),7.65(t,J＝9.5Hz,2H),7.53(d,J＝3.6Hz,1H),7.33(d,J＝3.6Hz,1H),7.08(d,J＝8.7Hz,2H),6.39(s,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.79(d,J＝17.1Hz,1H),4.53–4.34(m,5H),4.26(t,J＝7.0Hz,2H),4.05(s,1H),3.95(d,J＝11.1Hz,1H),3.28(s,3H),3.11(dd,J＝33.8,10.9Hz,8H),2.96–2.84(m,3H),2.67–2.53(m,4H),2.47–2.35(m,1H),2.03(dd,J＝17.7,12.2Hz,1H),1.87(s,2H).LCMS(ESI)C 48 H 48 F 3 N 10 O 5 S + [M+H] + Calculated 933.35, measured 933.4.
Example 385: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04516)
The title compound (GT-04516) (white solid, 58mg, yield 70.50%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.63(d,J＝9.7Hz,1H),11.01(d,J＝9.1Hz,1H),10.36(s,1H),8.82–8.70(m,1H),8.51–8.43(m,1H),8.38(t,J＝7.9Hz,1H),8.24–8.14(m,1H),7.84(dd,J＝15.8,8.2Hz,2H),7.79–7.65(m,3H),6.08(d,J＝8.6Hz,1H),5.15(dd,J＝14.0,4.9Hz,1H),4.57–4.41(m,4H),3.54(d,J＝10.2Hz,1H),3.15(d,J＝11.5Hz,2H),3.05–2.80(m,2H),2.71–2.56(m,2H),2.37(dd,J＝26.8,9.8Hz,3H),2.18–1.98(m,3H),1.62(d,J＝11.4Hz,6H).LCMS(ESI)C 36 H 36 F 3 N 6 O 6 + [M+H] + Calculated 705.26, measured 705.3.
Example 386: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04518)
The title compound (GT-04518) (white solid, 50mg, 59.34% yield) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.63(d,J＝8.7Hz,1H),11.03(s,1H),10.57(d,J＝63.4Hz,1H),8.76(d,J＝12.9Hz,1H),8.41(ddd,J＝25.9,16.4,8.9Hz,3H),8.23–8.17(m,1H),7.90(s,1H),7.71(d,J＝15.5Hz,2H),6.07(s,1H),5.18–5.12(m,1H),4.55(dd,J＝31.9,10.3Hz,4H),3.61(s,2H),3.08(s,3H),2.92(d,J＝11.9Hz,1H),2.62(d,J＝17.0Hz,1H),2.35(d,J＝13.4Hz,3H),2.15(d,J＝12.1Hz,1H),2.02(d,J＝5.2Hz,2H),1.62(d,J＝10.3Hz,6H).LCMS(ESI)C 36 H 35 F 4 N 6 O 6 + [M+H] + Calculated 723.25, measured 723.3.
Example 387: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04519)
The title compound (GT-04519) was obtained as a white solid (44 mg, 52.22% yield) according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.63(d,J＝9.4Hz,1H),11.03(s,1H),10.48(s,1H),8.82–8.65(m,1H),8.53–8.32(m,2H),8.19(d,J＝7.7Hz,1H),7.98(s,1H),7.78–7.61(m,2H),6.07(s,1H),5.15(d,J＝13.4Hz,1H),4.63–4.28(m,4H),3.80–3.43(m,2H),3.29–3.04(m,3H),2.93(t,J＝12.9Hz,1H),2.62(d,J＝16.1Hz,1H),2.33(s,3H),2.10(dd,J＝24.5,14.4Hz,3H),1.73–1.48(m,6H).LCMS(ESI)C 36 H 35 F 4 N 6 O 6 + [M+H] + Calculated 723.25, measured 723.3.
Example 388: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -6- (2-hydroxypropan-2-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04520)
The title compound (GT-04520) was prepared according to the method of scheme 11 (white solid, 45mg, yield 54.28%). 1 H NMR(400MHz,DMSO)δ12.39(d,J＝7.4Hz,1H),11.00(d,J＝10.5Hz,1H),10.77(s,1H),8.75(d,J＝11.8Hz,1H),8.56–8.41(m,1H),8.40–8.29(m,2H),8.16(d,J＝7.7Hz,1H),7.81(ddd,J＝21.4,13.4,6.8Hz,3H),7.60(d,J＝9.1Hz,1H),5.97(s,1H),5.22–5.06(m,1H),4.57–4.35(m,4H),3.57(d,J＝11.0Hz,1H),3.24–3.14(m,4H),2.92(dd,J＝17.5,5.5Hz,1H),2.62(d,J＝16.5Hz,1H),2.45–2.22(m,5H),2.06–1.98(m,1H),1.63(d,J＝8.5Hz,6H).LCMS(ESI)C 36 H 37 F 3 N 7 O 5 + [M+H] + Calculated 704.28, measured 704.3.
Example 389: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -6- (2-hydroxypropan-2-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04521)
The title compound (GT-04521) (white solid, 46mg, yield 54.17%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.38(s,1H),11.04(s,2H),8.75(d,J＝11.0Hz,1H),8.56–8.30(m,3H),8.16(d,J＝7.8Hz,1H),7.97(t,J＝6.9Hz,1H),7.74(d,J＝7.7Hz,1H),7.59(s,1H),5.98(s,1H),5.17(dd,J＝13.2,4.9Hz,1H),4.79(t,J＝11.6Hz,1H),4.69–4.39(m,4H),3.64(s,1H),3.35–3.21(m,4H),3.02–2.86(m,1H),2.56(d,J＝32.6Hz,2H),2.40(dd,J＝40.3,12.9Hz,4H),2.04(dd,J＝15.9,10.7Hz,1H),1.62(s,6H).LCMS(ESI)C 36 H 36 F 4 N 7 O 5 + [M+H] + Calculated 722.27, measured 722.3.
Example 390: preparation of N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -6- (2-hydroxypropan-2-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide (GT-04522)
The title compound (GT-04522) (white solid, 41mg, yield 48.28%) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.38(s,1H),11.03(s,1H),10.86(s,1H),8.75(d,J＝12.2Hz,1H),8.57–8.27(m,3H),8.16(d,J＝7.9Hz,1H),8.02(s,1H),7.72(d,J＝8.4Hz,1H),7.59(s,1H),5.97(s,1H),5.16(dd,J＝13.2,5.0Hz,1H),4.86(d,J＝51.4Hz,1H),4.63–4.26(m,4H),3.61(s,1H),3.35(s,4H),2.92(dd,J＝21.6,9.4Hz,1H),2.62(d,J＝16.7Hz,1H),2.44–2.10(m,5H),2.08–1.95(m,1H),1.62(s,6H).LCMS(ESI)C 36 H 36 F 4 N 7 O 5 + [M+H] + Calculated 722.27, measured 722.3.
Comparative example 1: preparation of 3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) -1-methylpiperidine-2, 6-dione (GT-04414)
The title compound (GT-04414) (white solid, 65mg, yield 81.55%) was obtained by the method of scheme 11. 1 H NMR(400MHz,MeOD)δ8.30(d,J＝27.6Hz,1H),8.16(s,1H),7.99–7.87(m,2H),7.82–7.68(m,2H),7.64(t,J＝7.9Hz,1H),7.56–7.40(m,2H),7.19(s,1H),6.97(d,J＝8.5Hz,1H),5.21(dd,J＝13.4,5.1Hz,1H),4.78(s,1H),4.60(q,J＝17.5Hz,2H),4.48(s,1H),3.95(d,J＝13.7Hz,5H),3.85(s,1H),3.44(dd,J＝33.4,21.9Hz,2H),3.14(d,J＝7.2Hz,3H),3.02–2.90(m,2H),2.87(d,J＝13.0Hz,3H),2.58–2.32(m,5H),2.24–2.11(m,1H),1.88(d,J＝13.6Hz,6H).LCMS(ESI)C 40 H 47 ClN 8 O 5 P + [M+H] + Calculated 785.31, measured 785.4.
Comparative example 2: preparation of 9-ethyl-6, 6-dimethyl-8- (4- (4- ((2- (1-methyl-2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (GT-04415)
The title compound (GT-04415) was prepared according to the method of scheme 11 (white solid, 20mg, yield 23.31%). 1 H NMR(400MHz,DMSO)δ12.84(s,1H),8.32(d,J＝8.2Hz,1H),8.04(d,J＝22.1Hz,2H),7.80(t,J＝19.8Hz,3H),7.61(dd,J＝8.2,1.4Hz,1H),7.36(s,1H),5.22(dd,J＝13.4,5.1Hz,1H),4.44(dd,J＝54.9,17.5Hz,4H),3.64(d,J＝38.9Hz,4H),3.32(d,J＝11.5Hz,6H),3.06–2.97(m,4H),2.89–2.78(m,3H),2.78–2.65(m,3H),2.48–2.36(m,1H),2.21(s,2H),2.11–1.99(m,1H),1.91(d,J＝10.0Hz,2H),1.77(s,6H),1.29(t,J＝7.5Hz,3H).LCMS(ESI)C 45 H 50 N 7 O 4 + [M+H] + Calculated 752.39, measured 752.4.
Comparative example 3: preparation of 3- (5- (3- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) propyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04458)
The title compound (GT-04458) (white solid, 23mg, yield 28.37%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.00(s,1H),10.96(d,J＝18.9Hz,2H),9.47(s,1H),8.34(d,J＝35.0Hz,2H),7.72–7.59(m,2H),7.55–7.39(m,4H),7.26(t,J＝7.5Hz,1H),6.97(s,1H),6.80(s,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.39(dd,J＝52.5,17.2Hz,2H),3.86(s,2H),3.82(s,3H),3.21(s,2H),3.07(s,3H),2.91(d,J＝12.8Hz,1H),2.81(s,2H),2.74(d,J＝4.6Hz,3H),2.61(d,J＝16.8Hz,1H),2.44–2.36(m,1H),2.25(d,J＝12.2Hz,1H),2.12(d,J＝31.5Hz,3H),2.04–1.90(m,3H),1.80(d,J＝13.6Hz,6H).LCMS(ESI)C 41 H 49 ClN 8 O 5 P + [M+H] + Calculated 799.32, measured 799.3.
Comparative example 4:8- (4- (4- (3- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) propyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ]]Preparation of carbazole-3-carbonitrile (GT-04457)
The title compound (GT-04457) (white solid, 41mg, yield 49.13%) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.82(s,1H),11.79(s,1H),10.99(s,1H),8.32(d,J＝8.2Hz,1H),8.07(s,1H),8.01(s,1H),7.70(d,J＝7.7Hz,1H),7.61(d,J＝8.2Hz,1H),7.51(s,1H),7.43(d,J＝7.7Hz,1H),7.36(s,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.39(dd,J＝51.1,17.3Hz,2H),3.65(d,J＝119.1Hz,7H),3.33(d,J＝11.0Hz,4H),3.18(s,2H),2.99–2.79(m,5H),2.73(q,J＝7.5Hz,2H),2.61(d,J＝16.6Hz,1H),2.44–2.34(m,1H),2.22(s,2H),2.09(s,2H),2.04–1.99(m,1H),1.93(s,2H),1.77(s,6H),1.30(t,J＝7.5Hz,3H).LCMS(ESI)C 46 H 52 N 7 O 4 + [M+H] + Calculated 766.41, measured 766.4.
Comparison ofExample 5:8- (4- (4- (2- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) ethyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ]]Preparation of carbazole-3-carbonitrile (GT-04512)
The title compound (GT-04512) was obtained as a white solid (37 mg, 43.13% yield) according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ12.85(s,1H),12.05(s,1H),10.99(s,1H),8.32(d,J＝8.2Hz,1H),8.07(s,1H),8.01(s,1H),7.72(d,J＝7.8Hz,1H),7.64–7.54(m,2H),7.48(d,J＝7.9Hz,1H),7.37(s,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.40(dd,J＝51.6,17.5Hz,2H),3.66(d,J＝130.3Hz,8H),3.34(d,J＝11.9Hz,5H),3.22(s,2H),2.94(dd,J＝22.2,9.0Hz,1H),2.84(t,J＝11.7Hz,2H),2.73(q,J＝7.4Hz,2H),2.61(d,J＝16.6Hz,1H),2.45–2.34(m,1H),2.24(s,2H),2.06–1.86(m,3H),1.77(s,6H),1.30(t,J＝7.5Hz,3H).LCMS(ESI)C 45 H 50 N 7 O 4 + [M+H] + Calculated 752.39, measured 752.5.
Comparative example 6: preparation of 3- (5- (2- ((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) ethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04513)
The title compound (GT-04513) was prepared according to the method of scheme 11 (white solid, 26mg, yield 32.62%). 1 H NMR(400MHz,DMSO)δ11.96(s,1H),11.10(s,1H),10.99(s,1H),9.35(s,1H),8.40(s,1H),8.27(s,1H),7.73(d,J＝7.8Hz,1H),7.68–7.53(m,2H),7.55–7.33(m,3H),7.24(t,J＝7.2Hz,1H),6.82(d,J＝58.5Hz,2H),5.12(dd,J＝13.3,5.2Hz,1H),4.39(dd,J＝51.8,17.4Hz,2H),3.89(s,2H),3.81(s,3H),3.39–3.18(m,5H),3.08–2.88(m,3H),2.82(d,J＝4.7Hz,3H),2.61(d,J＝17.2Hz,1H),2.45–2.36(m,1H),2.27(s,1H),2.19(s,1H),2.08–1.87(m,3H),1.80(d,J＝13.6Hz,6H).LCMS(ESI)C 40 H 47 ClN 8 O 5 P + [M+H] + Calculated 785.31, measured 785.3.
Comparative example 7: preparation of 3- (5- ((4- (4- ((1R, 2S) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) -1-methylpiperidine-2, 6-dione (GT-04561)
The title compound (GT-04561) (white solid, 16mg, yield 17.80%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.91(s,1H),9.12(s,1H),7.92–7.79(m,2H),7.74(d,J＝7.4Hz,1H),7.18–7.07(m,3H),6.84(d,J＝6.9Hz,2H),6.65–6.53(m,4H),6.48(dd,J＝8.3,2.3Hz,1H),6.25(d,J＝8.5Hz,2H),5.21(dd,J＝13.4,4.9Hz,1H),4.55–4.33(m,4H),4.16(d,J＝5.0Hz,1H),3.63(d,J＝12.2Hz,2H),3.29(s,2H),3.11(d,J＝10.2Hz,2H),3.05–2.87(m,9H),2.77(d,J＝17.9Hz,1H),2.41(dd,J＝13.0,8.8Hz,1H),2.06(ddd,J＝15.8,15.1,9.0Hz,2H),1.71(d,J＝7.2Hz,1H).LCMS(ESI)C 41 H 43 N 4 O 4 + [M+H] + Calculated 655.33, measured 655.4.
Comparative example 8: preparation of 3- (5- (2- (4- (4- ((1R, 2S) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) ethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04562)
The title compound (GT-04562) (white solid, 32mg, yield 35.61%) was prepared according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.98(s,1H),10.74(s,1H),9.13(s,1H),7.72(d,J＝7.8Hz,1H),7.53(s,1H),7.44(d,J＝7.8Hz,1H),7.14(dq,J＝14.0,6.9Hz,3H),6.85(d,J＝6.9Hz,2H),6.66–6.55(m,4H),6.49(dd,J＝8.3,2.3Hz,1H),6.27(d,J＝8.5Hz,2H),5.11(dd,J＝13.2,5.1Hz,1H),4.38(dd,J＝51.6,17.5Hz,2H),4.17(d,J＝4.9Hz,1H),3.64(dd,J＝38.3,11.6Hz,4H),3.38(s,2H),3.30(s,1H),3.23–3.07(m,4H),3.03–2.87(m,5H),2.60(d,J＝16.9Hz,1H),2.46–2.36(m,1H),2.15–1.93(m,2H),1.72(d,J＝7.1Hz,1H).LCMS(ESI)C 41 H 43 N 4 O 4 + [M+H] + Calculated 655.33, measured 655.3.
Comparative example 9: preparation of 3- (5- (2- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) ethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04563)
The title compound (GT-04563) was prepared according to the method of scheme 11 (white solid, 67mg, yield 74.92%). 1 H NMR(400MHz,DMSO)δ10.99(s,2H),8.49(s,1H),7.70(dd,J＝21.5,8.3Hz,3H),7.57(s,1H),7.52–7.40(m,3H),7.17(tt,J＝14.3,7.0Hz,5H),5.11(dt,J＝12.8,6.5Hz,2H),4.51–4.30(m,2H),3.76(s,2H),3.41–3.25(m,6H),2.91(dd,J＝21.6,9.3Hz,1H),2.61(d,J＝14.7Hz,3H),2.46–2.39(m,1H),2.26(t,J＝23.4Hz,2H),2.06–1.95(m,1H).LCMS(ESI)C 37 H 37 N 8 O 4 + [M+H] + Calculated 657.29, measured 657.3.
Comparative example 10: preparation of 3- (5- (3- (4- (4- ((1R, 2S) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) propyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04564)
The title compound (GT-04564) (white solid, 47mg, yield 51.26%) was obtained according to the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.98(s,1H),10.64(s,1H),9.12(s,1H),7.67(d,J＝7.8Hz,1H),7.49(s,1H),7.40(d,J＝7.9Hz,1H),7.19–7.05(m,3H),6.84(d,J＝6.9Hz,2H),6.61(dd,J＝11.8,8.8Hz,4H),6.48(dd,J＝8.3,2.3Hz,1H),6.25(d,J＝8.5Hz,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.37(dd,J＝50.7,17.3Hz,2H),4.16(d,J＝4.9Hz,1H),3.62(d,J＝11.7Hz,2H),3.50(d,J＝10.5Hz,2H),3.29(s,1H),3.16–2.86(m,9H),2.78(t,J＝7.3Hz,2H),2.60(d,J＝17.0Hz,1H),2.44–2.31(m,1H),2.15–1.94(m,4H),1.71(d,J＝7.3Hz,1H).LCMS(ESI)C 42 H 45 N 4 O 4 + [M+H] + Calculated 669.34, measured 669.4.
Comparative example 11: preparation of 3- (5- (3- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) propyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione (GT-04565)
The title compound (GT-04565) (white solid, 67mg, yield 73.44%) was obtained by the method of scheme 11. 1 H NMR(400MHz,DMSO)δ10.98(s,1H),10.72(s,1H),8.47(s,1H),7.76–7.60(m,3H),7.56–7.35(m,4H),7.25–7.07(m,5H),5.19–4.95(m,2H),4.38(ddd,J＝23.4,17.3,6.7Hz,2H),3.42(s,2H),3.26–3.16(m,2H),3.09(s,2H),2.96–2.87(m,1H),2.81(t,J＝7.4Hz,2H),2.70–2.52(m,3H),2.41(dd,J＝13.2,4.5Hz,1H),2.15(dd,J＝18.0,10.5Hz,4H),2.05–1.96(m,1H).LCMS(ESI)C 38 H 39 N 8 O 4 + [M+H] + Calculated 671.31, measured 671.3.
Biological Activity assay
Experimental reagents and materials
The experimental method comprises the following steps:
cell culture
In the cell culture medium of Table 4, at 5% CO 2 The tumor cells used in the present disclosure were cultured in 37℃incubators, respectively. All cells were identified as correct by STR and were mycoplasma negative by mycoplasma detection kit prior to the experiment.
TABLE 4 tumor cells and cell culture media used in the present disclosure
half-Inhibitory Concentration (IC) of compound against tumor cells 50 ) And (3) measuring:
IC's of the compounds of the present disclosure (including the compounds of Table 1, table 3 and the compounds of the examples) 50 The assay was performed using the Meinai Biol.S. Meilun Cell Counting Kit-8 kit. The method comprises the following specific steps: tumor cells were seeded in 96-well cell culture plates at the seeding densities of table 5, respectively. The next day, the test compounds of the present disclosure were subjected to 5-fold gradient dilution from the highest concentration of 10 μm, 10 concentrations were set from high to low, and then 0.5 μl of the diluted compounds of the present disclosure (including the compounds of table 1, table 3, and example compounds) was added to the inoculated 100 μl cells. After a period of treatment of cells with a compound of the present disclosure, cell activity assays were performed according to the instructions of the CCK-8 kit. The negative control was DMSO and the control was the corresponding commercial inhibitor (including Nabucasin (BBI 608), CAS number: 83280-65-3), ibrutinib ((Ibutinib), CAS number: 936563-96-1), GT-03308 compound (CAS number: 1679327-21-9), GT-03335 compound (CAS number: 1801765-04-7), GT-03336 compound (CAS number: 2160546-07-4), GT-03334 compound (CAS number: 1801747-42-1), enzalutamide (enzalutamide, CAS number: 915087-33-1), afatinib (afatinib, CAS number: 439081-18-2), origitinib (OSimitinib, CAS number: 1421373-65-0), AT7519 (CAS number: 844442-38-2), dasatinib (Dasatinib, CAS number: 302962-49-8); Abeli (Abemaciclib, CAS number 1231929-97-7); rabociclib (CAS number 1211443-58-1); pabociclib (CAS number 571190-30-2); bragg inib (CAS number 1197953-54-0); ai Leti Ni (alectrinib, CAS number 1256580-46-7); JQ-1 (CAS number 1268524-70-4); apatalone (Apabetalone, CAS number 1044870-39-4); feddatinib (Fedratinib, CAS number 936091-26-8); gefamtinib (Defactinib, CAS number 1073154-85-4); PND-1186 (CAS number 1061353-68-1); PF06650833 (CAS number 1817626-54-2); emawuertib (CAS number: 1801344-14-8); wineturala (ABT-199, venetoclax, CAS number: 1257044-40-8); ABT-263 (Navitocrax, CAS number 923564-51-6); and LDN-212854 (CAS No. 1432597-26-6)), cells were treated in the same manner as the presently disclosed compounds. Inhibition of cell growth by compounds of the present disclosure was plotted by Prism Graphpad software and compound IC of the present disclosure was counted therefrom 50 . The results are shown in tables 6-21 below.
Table 5: inoculation procedure and treatment time of tumor cells
Table 6: inhibitory Activity of Compounds of the presently disclosed examples designed based on STAT3 inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 7: inhibitory Activity of the presently disclosed example compounds designed based on BTK inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 8: inhibitory Activity of Compounds of the presently disclosed examples designed based on ER inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 9: inhibitory Activity of Compounds of the presently disclosed examples designed based on SHP2 inhibitors on tumor cell proliferation (IC 50 ,nM)
| Compound number/name | HCC827 | Ramos |
| GT-03335 | C | >10000 |
| GT-03322 | C | E |
| GT-03336 | D | >10000 |
| GT-03321 | D | - |
| GT-03334 | E | >10000 |
| GT-03320 | - | C |
Table 10: inhibitory Activity of Compounds of the presently disclosed embodiments designed based on AR inhibitors on tumor cell proliferation (IC 50 ,nM)
| Compound number/name | DU-145 | PC-3 |
| Enzalutamide | - | - |
| GT-02989 | C | A+ |
Table 11: inhibitory Activity of Compounds of the presently disclosed embodiments designed based on EGFR inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 12: inhibitory Activity of Compounds of the presently disclosed examples designed based on CDK9 inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 13: inhibitory Activity of Compounds of the presently disclosed examples designed based on BCR-ABL inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 14: inhibitory Activity of Compounds of the presently disclosed examples designed based on CDK4/6 inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 15: inhibitory activity of compounds of the presently disclosed embodiments designed based on ALK inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 16: inhibitory Activity of Compounds of the presently disclosed examples designed based on BET inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 17: inhibitory Activity of RET inhibitor-based Compounds of the presently disclosed embodiments on tumor cell proliferation (IC) 50 ,nM)
| Compound number/name | MV-4-11 |
| Fedratinib | A |
| GT-02755 | B |
| GT-02753 | A |
| GT-02746 | B |
Table 18: inhibitory Activity of Compounds of the presently disclosed examples designed based on FAK inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 19: inhibitory Activity of Compounds of the presently disclosed examples designed based on IRAK4 inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 20: inhibitory Activity of Compounds of the presently disclosed examples designed based on BCL-2 inhibitors on tumor cell proliferation (IC 50 ,nM)
| Compound number/name | CCRF-CEM | HCC827 | LNcap | MDA-MB-231 | MM.1R | MM.1S | SR |
| ABT-199 | >10000 | E | D | D | - | >10000 | C |
| ABT-263 | - | - | - | - | - | - | - |
| GT-03478 | A+ | A+ | A+ | A+ | A+ | A+ | A+ |
| GT-03479 | A+ | B | A+ | A+ | A+ | A+ | A+ |
Table 21: inhibitory activity of compounds of the presently disclosed embodiments designed based on ALK2 inhibitors on tumor cell proliferation (IC 50 ,nM)
| Compound number/name | Vcap |
| LDN-212854 (CAS number 1432597-26-6) | B |
| GT-03442 | B |
Table 22: inhibitory Activity of Compounds of the presently disclosed examples designed based on NTRK inhibitors on tumor cell proliferation (IC 50 ,nM)
Table 23: the inhibitory activity (IC) of the compounds of the examples of the present disclosure against tumor cell proliferation compared to the compounds of the comparative examples 50 ,nM)
| Compound number/name | MM.1R | CAL-62 | Jurkat |
| GT-03338 | C | D | B |
| GT-04512 (comparative example) | D | D | B |
| GT-04457 (comparative example) | E | E | B |
| GT-03319 | B | A+ | D |
| GT-04513 (comparative example) | B | D | D |
| GT-02742 | A+ | A+ | A+ |
| GT-04563 (comparative example) | A+ | E | D |
| GT-04565 (comparative example) | >10000 | >10000 | E |
| GT-03850 | A+ | A+ | A+ |
| GT-04562 (comparative example) | E | D | B |
| GT-04564 (comparative example) | D | D | B |
In tables 6-23, the symbols A+, A, B, C, D and E have the following meanings: a+ is less than or equal to 50nM;50nM < A < 100nM;100nM < B < 500nM;500nM < C.ltoreq.1000 nM;1000nM < D < 5000nM;5000nM < E.ltoreq.10000 nM.
The results show that the compounds of the invention (including the compounds of table 1, table 3 and examples) can inhibit the proliferation of tumor cells (as shown in tables 6-23), the inhibition effect is superior or equivalent to that of the corresponding positive control drug, and the degradation effect is superior to that of the corresponding positive control drug.
The foregoing has shown and described the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that various changes and modifications may be made therein without departing from the spirit and scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (41)
1. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof:
wherein the method comprises the steps of
A represents C (O), CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, or halo C 1-6 An alkyl group;
(R a ) m represents that the benzene ring is substituted by m R a Substituted, each R a The structural formulae are the following, which are identical or different and each independently of the others:
wherein,,
r represents chlorine, bromine, iodine, hydroxyl, leaving group, NR 7 R 8 Or a group W 1 ，
Wherein R is 7 And R is 8 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, C 2-6 alkynyl-C 1-6 Alkylene-, C 2-6 alkenyl-C 1-6 Alkylene-, optionally substituted 4-to 15-membered nitrogen containing heterocyclyl, or R 2a -R 1a -, wherein R is 1a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 2a Represents halogen, amino, hydroxy, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl or leaving group; and
group W 1 The structure of the following formula is shown:
wherein ring W 2 Represents optionally substituted nitrogen-containing heterocyclic groups, each ring W 3 Identical or different and each independently represents an optionally substituted nitrogen-containing heterocyclic group, t represents an integer 1 or 2, and ring W 4 Represents an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl;
R 5 and R is 6 Identical or different and each independently represents hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
or (b)
R and R 5 Together with the carbon atom to which they are attached form a carbonyl group, R 6 Represents hydrogen, optionally substituted methyl, or optionally substituted straight or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof;
(R b ) n Represents the benzene ring is substituted by n R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; and
m represents an integer 1, 2, 3 or 4, n represents an integer 0, 1, 2 or 3, and the sum of m and n is an integer 1, 2, 3 or 4; wherein when R and R 5 Together with the carbon atom to which they are attached form a carbonyl group and R 6 When representing hydrogen, m represents an integer 1, 2 or 3, n represents an integer 1, 2 or 3, and the sum of m and n is an integer 2, 3 or 4;
with the proviso that the following compounds and compounds of formula (I') are excluded:
When A represents CH 2 Or C (O), and R represents unsubstituted piperazinyl, m represents an integer 1 and n represents an integer 0;
when A represents CH 2 Or C (O), and R a Represents H 2 N-CH 2 -when m represents an integer 1 and n representsAn integer of 0;
when a represents C (O), and R represents bromine, m represents an integer 1 and n represents an integer 0; and
a compound of formula (I'):
wherein in formula (I'), A represents CH 2 Or C (O), and R represents unsubstituted piperidinyl or piperidinyl substituted with methylamino.
2. A compound of formula (I) as claimed in claim 1 or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, prodrug or polymorph thereof, which is also a compound of formula (I-1) or formula (I-2):
Therein A, R 1 、R 2 、R 3 、R 4 、R a 、R b M and n are as defined in claim 1.
3. A compound of formula (I) as claimed in claim 1 or 2, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, prodrug or polymorph thereof, wherein R represents:
chlorine, bromine, iodine, hydroxyl or a leaving group; or (b)
NR 7 R 8 Wherein R is 7 And R is 8 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, C 2-6 alkynyl-C 1-6 Alkylene-, C 2-6 alkenyl-C 1-6 Alkylene-, optionally substituted 4-to 15-membered nitrogen containingMonocyclic heterocyclyl, optionally substituted 4-to 15-membered nitrogen-containing bridged heterocyclyl, or optionally substituted 4-to 15-membered nitrogen-containing spiro heterocyclyl, or R 2a -R 1a -, wherein R is 1a Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 2a Represents halogen, amino, hydroxy, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl or a leaving group, each of said 4-to 15-membered nitrogen containing monocyclic heterocyclyl, said 4-to 15-membered nitrogen containing bridged heterocyclyl and said 4-to 15-membered nitrogen containing spiro heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of: deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, R 4a -R 3a -, or any combination thereof, wherein R 3a Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 4a Represents halogen, R 5a R 6a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 5a And R is 6a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; or (b)
Group W 1 Which is represented by the structure of the formula:
wherein ring W 2 Represents a 4-to 20-membered nitrogen-containing heterocyclic group, (R) a1 ) m1 Representing ring W 2 Optionally by m 1R a1 Substituted by radicals, each R a1 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 8a -R 7a -, wherein R is 7a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 8a Represents halogen, R 9a R 10a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 9a And R is 10a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; or (b)
Wherein each ring W 3 Identical or different and each independently represents a 4-to 20-membered nitrogen-containing heterocyclic group, t represents an integer 1 or 2, (R) a2 ) m2 Representing each ring W 3 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; and
ring W 4 Represents a 4-to 15-membered nitrogen-containing heterocyclic group, a 6-to 10-membered aryl group, or a 5-to 10-membered heteroaryl group, (R) a3 ) m3 Representing ring W 4 Optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxy, CHO, BAlkynyl, vinyl or leaving group, where R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group;
wherein m1, m2, m3 each independently represents an integer of 0 to 20.
4. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in claim 1 or 2 wherein
R represents NR 7 R 8 Wherein R is 7 And R is 8 Identical or different and each independently represents:
hydrogen, C 1-6 Alkyl, C 2-6 alkynyl-C 1-6 Alkylene-, C 2-6 alkenyl-C 1-6 An alkylene group; or (b)
Optionally substituted 4-to 15-membered nitrogen-containing monocyclic heterocyclyl, optionally substituted 4-to 15-membered nitrogen-containing bridged heterocyclyl, or optionally substituted 4-to 15-membered nitrogen-containing spiro heterocyclyl, e.g.,
piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazacycloheptyl, azacyclooctyl, diazacyclooctyl, azabicyclo [3.1.1] heptanyl, azabicyclo [2.2.1] heptanyl, azabicyclo [3.2.1] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [3.1.1] heptanyl, diazabicyclo [2.2.1] heptanyl, diazabicyclo [3.2.1] octanyl, diazabicyclo [2.2.2] octanyl, 3-azaspiro [5.5] undec-3-yl, 8-azaspiro [4.5] decane-4-yl, 2-oxa-8-azaspiro [4.5] decane-4-yl, or 3-methyl-2-oxa-8-azaspiro [4.5] decane-4-yl
R 2a -R 1a -, wherein R is 1a Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 2a Represents halogen, amino, hydroxy, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 An alkenyl group or a leaving group,
wherein each of the 4-to 15-membered nitrogen-containing monocyclic heterocyclyl, the 4-to 15-membered nitrogen-containing bridged heterocyclyl, and the 4-to 15-membered nitrogen-containing spiro heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of: deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, R 4a -R 3a -, or any combination thereof, wherein R 3a Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 4a Represents halogen, R 5a R 6a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 5a And R is 6a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; or (b)
R represents a group W 1 Which is represented by the structure of the formula:
wherein ring W 2 Represents a 4-to 20-membered nitrogen-containing heterocyclic group, for example,
piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazacycloheptyl, azacyclooctyl, diazacyclooctyl, azabicyclo [3.1.1] heptanyl, azabicyclo [2.2.1] heptanyl, azabicyclo [3.2.1] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [3.1.1] heptanyl, diazabicyclo [2.2.1] heptanyl, diazabicyclo [3.2.1] octanyl, diazabicyclo [2.2.2] octanyl, 3-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decane, 2-oxa-8-azaspiro [4.5] decane, or 3-methyl-2-oxa-8-azaspiro [4.5] decane, or a combination thereof
(R a1 ) m1 Representing ring W 2 Optionally by m 1R a1 Substituted by radicals, each R a1 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 8a -R 7a -, wherein R is 7a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 8a Represents halogen, R 9a R 10a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 9a And R is 10a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; or (b)
Group W 1 Represented by the structure of the formula:
wherein each ring W 3 Identical or different and each independently represents a 4-to 20-membered nitrogen-containing heterocyclylene group, for example,
piperidylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene, diazepanylene, azepanylene, azacyclooctylene, diazepanylene, azabicyclo [3.1.1] heptylene, azabicyclo [2.2.1] heptylene, azabicyclo [2.2.2] octanylene, diazabicyclo [3.1.1] heptanylene, diazabicyclo [2.2.1] octanylene, diazabicyclo [3.2.1] octanylene, diazabicyclo [2.2.2] octanylene, 3-azaspiro [5.5] undecylene, 8-azaspiro [4.5] decane, 2-oxa-8-azaspiro [4.5] decane, methyl-decane, or 3-oxa-8-spiro [4.5] decane
t represents an integer of 1 or 2, (R) a2 ) m2 Representing each ring W 3 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; and
ring W 4 Represents a 4-to 15-membered nitrogen-containing heterocyclic group, a 6-to 10-membered aryl group, or a 5-to 10-membered heteroaryl group, for example,
piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazacycloheptyl, azacyclooctyl, diazacyclooctyl, azabicyclo [3.1.1] heptanyl, azabicyclo [2.2.1] heptanyl, azabicyclo [3.2.1] octanyl, azabicyclo [2.2.2] octanyl, diazabicyclo [3.1.1] heptanyl, diazabicyclo [2.2.1] heptanyl, diazabicyclo [3.2.1] octanyl, diazabicyclo [2.2.2] octanyl, 3-azaspiro [5.5] undecyl, 8-azaspiro [4.5] decane, 2-oxa-8-azaspiro [4.5] decane, 3-methyl-2-oxa-8-azaspiro [4.5] decane, phenyl, naphthyl, furanyl, isoxazolyl, and the like oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo [2,1,3] oxadiazolyl, benzo [2,1,3] thiadiazolyl, benzo [1,2,3] thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-a ] pyridyl, 1H-pyrrolo [3,2-b ] pyridyl, 1H-pyrrolo [2,3-b ] pyridinyl, pyrrolo [2,1-b ] thiazolyl, or imidazo [2,1-b ] thiazolyl, or
(R a3 ) m3 Representing ring W 4 Optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, leaving group, amino, hydroxy, mercapto, cyano, carboxyl, CHO, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxyl, CHO, ethynyl, vinyl or leaving group, wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group;
wherein m1, m2, m3 each independently represents an integer of 0 to 20.
5. A compound of formula (I) as claimed in claim 1 or 2, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, prodrug or polymorph thereof, wherein R represents the following group:
chlorine, bromine, iodine, hydroxy, -N 3 Sulfonate groups, e.g. methanesulfonyloxy (MsO-), trifluoromethanesulfonyl (TfO-) or p-toluenesulfonyloxy (TsO-), NH 2 Or (b)
6. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in claim 1 or 2 wherein R 5 And R is 6 Each independently represents:
hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight or branched C 2-30 An alkyl group, a hydroxyl group,
wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof; and
hydrogen of the methyl group and the C 2-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
7. A compound of formula (I) as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof, wherein R and R 5 Together with the carbon atoms to which they are attached form a carbonyl group.
8. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in any one of claims 1-2 and 6-7 wherein R 6 The structure of the following formula is shown:
-C 1-30 an alkyl group;
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -(R c -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -(R d -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R c -R d -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -R c -(C(R a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
Wherein each group R c Selected from O, N (R) e )、C(O)、C(O)O、OC(O)、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 An alkyl group; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 5-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 5-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuteriumSubstituted C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof;
the C is 1-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, or optionally deuterated C 1-6 alkyl-C (O) NH-; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
9. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in claim 8 wherein R 6 The structure of the following formula is shown:
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(N(R e )-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(C(O)N(R e )-
(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -C(O)N(R e )-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)N(R e )-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 -C(O)-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 Arylene- (C (R) a8 )(R a9 )) n3 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heterocyclylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heteroarylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 - (cycloalkylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
Wherein each R e Independently represent H or C 1-6 An alkyl group;
the cycloalkylene, the arylene, the heterocyclylene and the heteroarylene are each independently optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, or optionally deuterated C 1-6 alkyl-C (O) NH-; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
10. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in claim 8 wherein R 6 The following groups are represented:
H. fluorine, chlorine, bromine, iodine, -CH 3 、-CH 2 -CH 3 、-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -CH 3 、-(CH 2 ) 7 -CH 3 、-(CH 2 ) 8 -CH 3 、-(CH 2 ) 9 -CH 3 、-(CH 2 ) 10 -CH 3 、-(CH 2 ) 11 -CH 3 、-(CH 2 ) 12 -CH 3 、-(CH 2 ) 13 -CH 3 、-(CH 2 ) 14 -CH 3 、-(CH 2 ) 15 -CH 3 、-(CH 2 ) 16 -CH 3 、-(CH 2 ) 17 -CH 3 、-(CH 2 ) 18 -CH 3 、-(CH 2 ) 19 -CH 3 、-(CH 2 ) 20 -CH 3 、-(CH 2 ) 21 -CH 3 、-(CH 2 ) 22 -CH 3 、-(CH 2 ) 25 -CH 3 、-(CH 2 ) 29 -CH 3 ；-CH 2 -O-CH 3 、-CH 2 -O-CH 2 -CH 3 、-CH 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 11 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 12 -CH 3 、-(CH 2 ) 3 -O-CH 3 、-(CH 2 ) 3 -O-CH 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 4 -O-CH 3 、-(CH 2 ) 4 -O-CH 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 5 -O-CH 3 、-(CH 2 ) 5 -O-CH 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -O-CH 3 、-(CH 2 ) 6 -O-CH 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 7 -O-CH 3 、-(CH 2 ) 7 -O-CH 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 8 -O-CH 3 、-(CH 2 ) 8 -O-CH 2 -CH 3 、-(CH 2 ) 8 -O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-CH 3 、-CH(CH 3 )-O-CH 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 9 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 10 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 9 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 10 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 4 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 CH 3 、-(CH 2 ) 1 -N(R e )-CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 11 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 1 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 9 -CH 3 、-CH 2 C(O)NHCH 3 、-(CH 2 ) 2 C(O)NHCH 2 CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 C(O)NH(CH 2 ) 7 -CH 3 、U-(CH 2 ) 9 C(O)NH(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 C(O)NH(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -O-CH 2 -CH 3 、-CH 2 NHC(O)CH 3 、-(CH 2 ) 2 NHC(O)CH 2 CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 9 NHC(O)(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 NHC(O)(CH 2 ) 9 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 4 NHC(O)CH 3 、-CH 2 -piperidinyl-CH 3 、-CH 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperidinyl-CH 3 、-(CH 2 ) 3 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -sub-piprazolePyridyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperidinyl-CH 3 、-(CH 2 ) 4 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperidinyl-CH 3 、-(CH 2 ) 5 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperidinyl-CH 3 、-(CH 2 ) 6 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperidinyl-CH 3 、-(CH 2 ) 7 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperidinyl-CH 3 、-(CH 2 ) 8 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl group-CH 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -piperazinylene-CH 3 、-CH 2 -piperazinylene-CH 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperazinylene-CH 3 、-(CH 2 ) 2 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperazinylene-CH 3 、-(CH 2 ) 3 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -sub-piperazinyl-CH 3 、-(CH 2 ) 4 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperazinylene-CH 3 、-(CH 2 ) 5 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperazinylene-CH 3 、-(CH 2 ) 6 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperazinylene-CH 3 、-(CH 2 ) 7 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperazinylene-CH 3 、-(CH 2 ) 8 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 6 -CH 3 Or- (CH) 2 ) 8 -piperazinylene- (CH) 2 ) 7 -CH 3 ；
Wherein said piperidinyl and said piperazinyl independently of each other are optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, nitro, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof;
CH in said group 3 Hydrogen and one or more CH 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 Alkyl group-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
each R is e Independently represent H or C 1-6 An alkyl group; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
11. A compound of formula (I) as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof, selected from:
3- (5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (chloromethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (iodomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (aminomethyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (aminomethyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (aminomethyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl 4-methylbenzenesulfonate;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl mesylate;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl triflate;
3- (5- (bromomethyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (bromomethyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (bromomethyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3- (5- ((3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3- (5- ((3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione; 3- (5- ((3, 8-diazabicyclo [ 3.2.1)]Octan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3- (5- ((2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione; 3- (5- ((2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione; 3- (1-oxo-5- ((piperazin-1-yl) -2,2,3,3,5,5,6,6-d) 8 ) Methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((2, 6-dimethylpiperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((3, 5-dimethylpiperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-chloro-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-chloro-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-chloro-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-1-oxo-5- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (chloromethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (iodomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5-fluoro-4- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-4- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-4- (hydroxymethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (aminomethyl) -5-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (aminomethyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (aminomethyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl 4-methylbenzenesulfonate;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl mesylate;
(2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl triflate;
3- (4- (bromomethyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (bromomethyl) -5-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (bromomethyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-4- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-4- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5-bromo-4- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((3, 6-diazabicyclo [3.1.1] heptan-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((3, 6-diazabicyclo [3.1.1] heptan-6-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((3, 8-diazabicyclo [3.2.1] oct-8-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((3, 8-diazabicyclo [3.2.1] oct-3-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((2, 5-diazabicyclo [2.2.2] oct-2-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((piperazin-1-yl) -2,2,3,3,5,5,6,6-d) 8 ) Methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((2, 6-dimethylpiperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((3, 5-dimethylpiperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-chloro-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (5-fluoro-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (5-chloro-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (5-bromo-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-chloro-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((R) -3-aminopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((S) -3-aminopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4-aminopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-5- (piperidin-4-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (azetidin-3-ylmethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((R) -3-aminopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((S) -3-aminopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4-aminopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione 3- (1-oxo-4- (piperazin-1-ylmethyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (azetidin-3-ylmethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- (chloromethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (iodomethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (hydroxymethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (hydroxymethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (hydroxymethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (hydroxymethyl) isoindoline-1, 3-dione;
5- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
(2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl 4-methylbenzenesulfonate;
(2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl methanesulfonate;
(2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl triflate;
6- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
4-bromo-6- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((3, 6-diazabicyclo [ 3.1.1)]Heptan-3-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-13-diketones; 5- ((3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 5- ((3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 5- ((3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 5- ((2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 5- ((2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 2- (2, 6-Dioxopiperidin-3-yl) -5- ((piperazin-1-yl) -2,2,3,3,5,5,6,6-d 8 ) Methyl) isoindoline-1, 3-dione;
5- ((2, 6-dimethylpiperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((3, 5-dimethylpiperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4-chloro-2- (2, 6-dioxopiperidin-3-yl) -6- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4-chloro-2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
5-chloro-2- (2, 6-dioxopiperidin-3-yl) -6- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4- (chloromethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- (iodomethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- (hydroxymethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-4- (hydroxymethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- (hydroxymethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- (hydroxymethyl) isoindoline-1, 3-dione;
4- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione;
4- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
4- (aminomethyl) -2- (2, 6-dioxopiperidin-3-yl) -7-fluoroisoindoline-1, 3-dione;
(2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl 4-methylbenzenesulfonate;
(2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl methanesulfonate;
(2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl triflate;
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -7-fluoroisoindoline-1, 3-dione;
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione;
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
4-bromo-7- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6-bromo-4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoles -a 1, 3-dione; 4- ((3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 4- ((3, 8-diazabicyclo [ 3.2.1)]Octane-8-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 4- ((3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 4- ((2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 4- ((2, 5-diazabicyclo [ 2.2.2)]Octane-2-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 2- (2, 6-Dioxopiperidin-3-yl) -4- ((piperazin-1-yl) -2,2,3,3,5,5,6,6-d 8 ) Methyl) isoindoline-1, 3-dione;
4- ((2, 6-dimethylpiperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((3, 5-dimethylpiperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-7- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4-chloro-2- (2, 6-dioxopiperidin-3-yl) -7- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -7- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-4- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
5-chloro-2- (2, 6-dioxopiperidin-3-yl) -4- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -4- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-4- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
6-chloro-2- (2, 6-dioxopiperidin-3-yl) -4- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
6-bromo-2- (2, 6-dioxopiperidin-3-yl) -4- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
5- (((R) -3-aminopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((S) -3-aminopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione; 5- ((4-aminopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (piperazin-1-ylmethyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (piperidin-4-ylmethyl) isoindoline-1, 3-dione;
5- (azetidin-3-ylmethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- (((R) -3-aminopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- (((S) -3-aminopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4-aminopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- (azetidin-3-ylmethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
(E) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enoic acid;
(E) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) but-2-enoic acid;
(E) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enoic acid;
(E) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) piperazin-1-yl) but-2-enoic acid; 3- (5- ((4- (3-hydroxypropyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (3-hydroxypropyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (3-hydroxypropyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (3-hydroxypropyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- ((4- (3-bromopropyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (3-bromopropyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (3-bromopropyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (3-bromopropyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (5- ((4-hydroxypiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4-hydroxypiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4-hydroxypiperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4-hydroxypiperidin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- ((4-bromopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4-bromopiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4-bromopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4-bromopiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (5- (((2-bromoethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((2-bromoethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- (((2-bromoethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- (((2-bromoethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (5- ((methyl (piperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((methyl (piperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((methyl (piperidin-4-yl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((methyl (piperidin-4-yl) amino) methyl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((4- (piperazin-1-yl) piperidin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((4- (piperazin-1-yl) piperidin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((4- (piperidin-4-yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((4- (piperidin-4-yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((4-phenylpiperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((4-phenylpiperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4-phenylpiperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4-phenylpiperazin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- ((4- (4-bromophenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4-bromophenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (4-bromophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (4-bromophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((4- (pyridazin-3-yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((4- (pyridazin-3-yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (pyridazin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4- (pyridazin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- ((4- (6-chloropyridazin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (6-chloropyridazin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (6-chloropyridazin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (6-chloropyridazin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3-fluoropiperidin-4-ylmethane sulfonate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) -3-fluoropiperidin-4-yl methanesulfonate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3-fluoropiperidin-4-ylmethane sulfonate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) -3-fluoropiperidin-4-ylmethane sulfonate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl triflate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-3-yl triflate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl trifluoromethanesulfonate;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) piperidin-3-yl trifluoromethanesulfonate;
3- (5- ((4- (6-aminopyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (6-aminopyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (6-aminopyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (6-aminopyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (5- ((4- (azetidin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (azetidin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (azetidin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (azetidin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((3- (piperazin-1-yl) azetidin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((3- (piperazin-1-yl) azetidin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (piperazin-1-yl) azetidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((3- (piperazin-1-yl) azetidin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- ((4-methylpiperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4-methylpiperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4-methylpiperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4-methylpiperazin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- ((4- (difluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (difluoromethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (difluoromethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (difluoromethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((piperidin-4-ylamino) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((piperidin-4-ylamino) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((piperidin-4-ylamino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((piperidin-4-ylamino) methyl) isoindoline-1, 3-dione;
3- (5- ((4- (2-aminoethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (2-aminoethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (2-aminoethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((4- (2-aminoethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((4-propylpiperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((4-propylpiperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4-propylpiperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4-propylpiperazin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- (((2-hydroxyethyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((2-hydroxyethyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((2-hydroxyethyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- (((2-hydroxyethyl) amino) methyl) isoindoline-1, 3-dione;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxylic acid;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidine-4-carboxylic acid;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxylic acid;
1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) piperidine-4-carboxylic acid;
1'- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) - [1,4' -bipiperidine ] -4-carboxylic acid;
1'- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) - [1,4' -bipiperidine ] -4-carboxylic acid;
1'- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) - [1,4' -bipiperidine ] -4-carboxylic acid;
1'- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) methyl) - [1,4' -bipiperidine ] -4-carboxylic acid;
3- (5- ((4-ethynyl piperidin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4-ethynyl piperidin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4-ethynylpiperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((4-ethynylpiperidin-1-yl) methyl) isoindoline-1, 3-dione;
3- (1-oxo-5- ((3- (piperazin-1-yl) piperidin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-4- ((3- (piperazin-1-yl) piperidin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- ((3- (piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
3- (5- (((4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((4-methylpiperidin-4-yl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- (((4-methylpiperidin-4-yl) amino) methyl) isoindoline-1, 3-dione;
3- (5- (((3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4- (((3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindoline-5-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindoline-5-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindoline-5-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-1-oxoisoindoline-4-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindoline-4-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindoline-4-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindoline-5-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindoline-5-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindoline-5-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-1, 3-dioxoisoindoline-4-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindoline-4-carbaldehyde;
2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindoline-4-carbaldehyde;
3- (4-bromo-6- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5-bromo-6- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-6- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (bromomethyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (bromomethyl) -5-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (bromomethyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-7- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5-bromo-7- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-7- (bromomethyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7- (bromomethyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7- (bromomethyl) -5-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7- (bromomethyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4-bromo-6- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
5- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-7- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6-bromo-4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -7-fluoroisoindoline-1, 3-dione;
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione; and
4- (bromomethyl) -2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione.
12. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof:
PBM-R f -LIN-ULM
formula (II)
Wherein PBM-R f -representing a targeting moiety capable of binding to a protein, ULM representing a ligand moiety capable of binding to E3 ubiquitin ligase, LIN being a linking moiety, PBM-R f -covalently linking ULM through the group LIN;
ULM represents the structure of the following formula (ULM):
wherein the method comprises the steps of
A represents CO or CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, or halo C 1-6 An alkyl group;
(R b ) n represents the benzene ring optionally substituted by n R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl;
n represents an integer of 0, 1, 2 or 3;
LIN represents the structure of the formula:
wherein R is 5 And R is 6 Identical or different and each independently represents hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight-chain or branched C 2-30 Alkyl, wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, cyano, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
R f represents a bond, -O-, -N (R) g )-、-NHC(O)-R h -W 5 -*、-C(O)NH-R h -W 5 -*、-NHC(O)-W 5 -*、-C(O)NH-W 5 -*、-NHC(O)-*、-C(O)NH-*、-O-R h -W 5 -*、-O-W 5 -*、-O-R h -N(R i )-*、-N(R g )-R h -N(R i )-*、-W 5 -、-W 5 -N(R g )-*、-N(R g )-W 5 -*、-N(R g )-W 5 -N(R i )-*、-R h -W 5 -*、-R h -C(O)-W 5 -*、-C(O)-W 5 -*、-R h -C(O)NH-R j -W 5 -*、-R h -NHC(O)-R j -W 5 -*、-R h -C(O)NH-*、-R h -NHC(O)-*、-R h -、-R h -N(R i ) -, or
Wherein the radical W 5 The structure of the following formula is shown:
wherein each ring W 6 Identical or different and each independently represents a nitrogen-containing heterocyclylene group, t1 represents an integer 1 or 2, (R) a2 ) m2 Representing each ring W 6 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m2 represents an integer of 0 to 20;
each ring W 7 Identical or different and each independently represents a nitrogen-containing heterocyclylene, arylene, or heteroarylene group, t2 represents an integer 0 or 1, (R) a3 ) m3 Representing each ring W 7 Independently optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein
R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m3 represents an integer of 0 to 20; and
R g and R is i Each independently represents hydrogen or C 1-6 Alkyl, R h And R is j Each independently represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, and the symbol represents the point of attachment to LIN;
wherein, when PBM represents the following structural formula:
and at the same time-R f -LIN-representation
Wherein the symbols denote the points of attachment to the ULM, (R) b ) n The benzene ring of formula (ULM) is substituted with 1, 2 or 3R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl;
provided that the following compounds were excluded:
3- (4- ((3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) pyrrolidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) azetidin-3-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione; and
2- (2, 6-dioxopiperidin-3-yl) -5- ((3- (4- (6- (6- (2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) azetidin-1-yl) methyl) isoindoline-1, 3-dione.
13. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to claim 12 wherein the PBM-R f -representing a small molecule ligand binding to: epidermal growth factor receptor (epidermal growth factor receptor, EGFR), cyclin-dependent kinase 4/6 (Cyclin-dependent kinase 4/6, CDK 4/6), anaplastic lymphoma kinase (anaplastic lymphoma kinase, ALK), activin receptor-like kinase 2 (activin receptor-like kinase 2, ALK 2), fibroblast growth factor receptor (fibroblast growth factor receptors, FGFRs), proto-oncogene tyrosine protein kinase receptor RET (proto-oncogene tyrosine-protein kinase receptor RET), focal adhesion kinase (Focal adhesion kinase, FAK), breakpoint cluster region (breakpoint cluster region, BCR) -Abelson leukemia virus (Abelson leukemia virus, ABL) (BCR-ABL) tyrosine kinase, bruton tyrosine kinase (Bruton tyrosine kinase, BTK), androgen receptor (Androgen receptor, AR), estrogen receptor (Estrogen receptor, ER), bromodomain and terminal ectodomain proteins (Bromodomain and extra-terminal domain protein, BET), interleukin-1 receptor-associated kinase 4 (Interleukin-1 receptor-associated kinase, irak 4), cyclin-dependent kinase 9 (cdk 9), histone lysine N-methyltransferase EZH2 (history-lysine N-methyltransferase EZH, EZH 2), neurotrophin receptor tyrosine kinase (neurotrophic receptor tyrosine kinase, NTRK), src homology 2-domain-containing protein tyrosine phosphatase (Src homology 2 domain containing protein tyrosine phosphatase,SHP2), poly (ADP-ribose) polymerase (PARP), signal transcripts and transcriptional activator protein 3 (signal transducers and activators of transcription 3, STAT 3), FMS-like tyrosine kinase 3 (FMS-like tyrosine kinase 3, FLT 3), BCL-2 (B cell lymph) oma-2) family proteins, SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS Ras/Rac guanine nucleotide exchange factor 1; SOS 1) or GTPase KRas (GTPase KRas; KRAS).
14. The compound of formula (III) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof of claim 12, wherein the PBM comprises a structure selected from the following formulas:
wherein the method comprises the steps of
(R 1 ) p1 The benzene ring in the formula (PBM-1) is substituted with p 1R 1 Substituted, each R 1 The same or different and each independently represents halogen, hydroxy, NH 2 、NO 2 Cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 2 ) p2 the quinazoline ring in the formula (PBM-1) is substituted with p 2R 2 Substituted, each R 2 Identical or different and each independently represents halogen, NO 2 Cyano, halo C 1-6 Alkyl, C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy, halo C 1-10 Alkoxy, -O-optionally substituted heterocyclyl, or-NHC (O) R 3 Wherein R is 3 Is C 1-10 Alkyl, deuterated C 1-10 Alkyl or C 2-10 Alkenyl radicals, e.g. R 2 Represents methyl, methoxy,
For example->
p1 represents an integer 1, 2, 3, 4 or 5;
p2 represents an integer of 1, 2, or 3;
(R 4 ) p3 the benzene ring in the formula (PBM-2) is substituted with p 3R 4 Substituted, each R 4 Identical or different and each independently represents halogen, nitro, cyano, halo C 1-6 Alkyl, C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Alkoxy or-NHC (O) R 15a Wherein R is 15a Is C 1-10 Alkyl, deuterated C 1-10 Alkyl or C 2-10 Alkenyl radicals, e.g. R 4 Represents methyl, methoxy, nitro or
p3 represents an integer 1, 2, 3 or 4;
(R 5 ) p4 the 1H-indole ring in the formula (PBM-2) is substituted with p 4R 5 Substituted, p4 represents an integer of 0, 1, 2 or 3, and each R 5 Identical or different and each independently represents C 1-10 Alkyl or deuterated C 1-10 An alkyl group;
R 6 represents hydrogen, C 1-10 Alkyl or deuterated C 1-10 An alkyl group;
(R 7 ) p5 the benzene ring in the formula (PBM-3) is substituted with p 5R 7 Substituted, each R 7 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, NO 2 、NH 2 Or cyano;
p5 represents an integer of 0, 1, 2, 3, 4 or 5;
R 8 represents substituted or unsubstituted C 3-15 Cycloalkyl groups such as cyclopentyl;
(R 9 ) p6 the benzene ring in the formula (PBM-4) is substituted with p 6R 9 Substituted, each R 9 Identical or different and each independently represents halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, NO 2 、NH 2 、C 1-6 Alkoxy, halo C 1-6 Alkoxy, or cyano;
p6 represents an integer of 2, 3, 4 or 5;
R 10 represent C 6-10 Aryl, or heteroaryl comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 The aryl and the heteroaryl are each optionally substituted with one or more R b1 Substitution, each R b1 The same or different and are each independently halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 11 ) p7 the benzene ring and the pyridine ring in the formula (PBM-5) are each optionally substituted with p 7R 11 Substituted, each p7 is the same or different and each independently represents an integer of 0, 1, 2 or 3, and each R in the formula (PBM-5) 11 Identical or different and each independently represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
R 12 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
r in formula (PBM-6) 13 Represents hydrogen, C 1-10 Alkyl (e.g
) Deuterated C 1-10 Alkyl or halo C 1-10 An alkyl group;
R 14 representation of
Wherein (R) b2 ) p8 Represents the piperidine ring optionally substituted by p 8R b2 Substituted, each R b2 Identical or different and each independently represents deuterium, halogen, hydroxy, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, NO 2 、NH 2 Or cyano, p8 represents an integer 1, 2, 3, 4 or 5;
ring A in formula (PBM-7) represents C 6-10 Aryl or 5-to 20-membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms selected from N, O and S, said ring A optionally being substituted with one or more R b3 Substitution, each R b3 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, C 2-6 Alkenyl, or C 2-6 Alkynyl;
ring B in formula (PBM-7) represents C 3-15 Cycloalkyl or 3-to 20-membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, wherein the ring B is optionally substituted with one or more R b4 Substitution, each R b4 Identical or different and are each independently deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
ring C in formula (PBM-7) represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, said ring C optionally being substituted with one or more R b5 Substitution, each R b5 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
r in formula (PBM-8) 15 Represents a 4-to 20-membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, wherein the heterocyclic group is optionally substituted with one or more R b6 Substitution, each R b6 The same or different and are each independently halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group; (R) 16 ) p9 The benzene ring in the formula (PBM-8) is substituted with p 9R 16 Substituted, each R 16 Identical or different and each independently represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 Alkyl, p9 represents an integer 1, 2, 3 or 4;
x of the formula (PBM-9) 1 Represents N or CR b7 Wherein R is b7 Is hydrogen or represents amino, X 2 Represents N or CR 17 Wherein R is 17 Is hydrogen or represents a bond and X 3 Represents CH or N;
R 18 and R is 19 Each independently represents hydrogen or represents a bond;
(R 20 ) p10 the benzene ring in the formula (PBM-9) is substituted with p 10R 20 Substituted, each R 20 Identical or different and each independently represents-O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC (O) -heteroaryl, -C 1-3 alkylene-C (O) NH-heteroaryl or halogen, said aryl and heteroaryl each independently being optionally substituted with one or more R b8 Substitution, each R b8 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p10 represents an integer of 1, 2, 3 or 4;
R 21 represents bond, deuterium, hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, or C 1-6 An alkoxy group;
R 22 represents hydrogen, halogen, cyano, or amino;
Wherein R is 17 、R 18 、R 19 And R is 21 Not both hydrogen and R 17 、R 18 、R 19 And R is 21 Not simultaneously being a bond, R 17 、R 18 、R 19 And R is 21 Represents a key, wherein
When R is 18 When the bond is represented, R is the same as 18 The ring carbon atoms to which they are attached being directly attached R f ，X 2 Represents CH or N, and R 19 Is hydrogen and R 21 Not a bond;
when X is 2 Represents CR 17 Wherein R is 17 When the bond is represented, R is the same as 17 The ring carbon atoms to which they are attached being directly attached R f And R is 18 And R is 19 Are all hydrogen and R 21 Not a bond;
when R is 19 When the bond is represented, R is the same as 19 The ring nitrogen atom being bound directly to R f ，X 2 Represents N or CH, and R 18 Is hydrogen and R 21 Not a bond; and
when R is 21 When the bond is represented, R is the same as 21 The ring carbon atoms to which they are attached being directly attached R f And X is 2 Represents N or CH and R 18 And R is 19 Are all hydrogen;
(R 23 ) p11 the cyclopentene ring in the formula (PBM-10) is substituted with p 11R 23 Substituted, each R 23 Identical or different and each independently represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 Alkyl, p11 represents an integer of 1, 2, 3, or 4;
(R 24 ) p12 the pyridine in the formula (PBM-10) is substituted with p 12R 24 Substituted, each R 24 Identical or different and each independently represents halogen, -C 1-3 alkylene-OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 Alkyl, p12 represents an integer of 1, 2, or 3;
R 25 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
x in formula (PBM-11) 4 Represents CR 26 Or a fragment
Wherein the symbol # denotes a symbol denoted by X 4 Adjacent N's connection points, the symbol # denotes X 5 And R is 26 Represents deuterium, hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, -C (O) -deuterated C 1-6 Alkyl or-C (O) NR b9 R b10 Wherein R is b9 、R b10 Identical or different and each independently represents hydrogen, C 1-6 Alkyl or deuterated C 1-6 An alkyl group;
x in formula (PBM-11) 5 Represents N or CR 27 Wherein R is 27 Represents hydrogen, deuterium, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
X 6 and X 7 Each independently represents CH or N;
R 28 represents a bond or an optionally substituted heteroarylene (e.g., a halogen substituted heteroarylene);
R 29 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, or optionally substituted C 3-7 Cycloalkyl;
R 30 and R is 31 Identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-12) 32 Represents hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
R 33 represents hydrogen, cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
(R 34 ) p13 the benzene ring in the formula (PBM-13) is substituted with p 13R 34 Substituted, each R 34 The radicals are identical or different and each independently represents halogen, hydroxy, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
p13 represents an integer of 1, 2, 3, 4 or 5;
R 35 represents NR b11 R b12 Wherein R is b11 、R b12 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
(R 36 ) p14 the benzene ring in the formula (PBM-14) is optionally substituted with p 14R 36 Substituted, p14 represents an integer of 1, 2 or 3, each R in the formula (PBM-14) 36 The radicals are identical or different and each independently represents halogen, amino, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
R 37 represents hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 An alkyl group;
x in the formula (PBM-15) 8 、X 9 、X 10 、X 11 And X 12 Identical or different and each independently represents N or CH;
R 38 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
R 39 represents-C (O) NHR b13 、-NHC(O)-R b13 、-S(O) 2 NHR b13 、-N(R b14 )S(O) 2 R b13 、-S(O) 2 R b13 or-P (O) (R b13 ) 2 Wherein each R is b13 Identical or different and each independently represents C 1-6 Alkyl or deuterated C 1-6 Alkyl, R b14 Represents hydrogen or C 1-6 An alkyl group;
(R 40 ) p15 the said compound of formula (PBM-15) containing X 9 And X 10 Optionally p 15R' s 40 Substituted, each R 40 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p15 represents an integer of 0, 1, 2, 3 or 4;
R 41 represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 42 ) p16 the benzene ring in the formula (PBM-16) is optionally substituted with p 16R 42 Substituted, each R in formula (PBM-16) 42 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
each p16 is the same or different and each independently represents an integer of 0, 1, 2, 3 or 4;
(R 43 ) p17 the benzene ring in the formula (PBM-17) is substituted with p 17R 43 Substituted, p17 represents an integer of 0, 1, 2, 3 or 4, each R in the formula (PBM-17) 43 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 44 ) p18 the benzene ring in the formula (PBM-18) is optionally substituted with p 18R 44 Substituted, each R 44 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p18 represents an integer of 0, 1, 2, 3 or 4;
(R 45 ) p19 the 4-oxo-3, 4-dihydroquinazoline ring in the formula (PBM-18) is substituted with p19 Rs 45 Substituted, each R 45 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p19 represents an integer 1, 2, 3 or 4;
(R 46 ) p20 the benzene ring in the formula (PBM-19) is substituted with p 20R 46 Substituted, each R 46 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p20 represents an integer of 1, 2, 3, 4 or 5;
R 47 represents halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 48 ) p21 the quinoline ring in the formula (PBM-20) is substituted with p 21R 48 Substituted, each R 48 Identical or different and each independently represents halogen, cyano, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p21 represents an integer of 1, 2, 3 or 4;
(R 49 ) p22 the benzene ring in the formula (PBM-20) is substituted with p 22R 49 Substituted, each R 49 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p22 represents an integer 2, 3 or 4;
r in formula (PBM-21) 50 represents-NHC (O) -or-C (O) NH-;
R 51 represents-NH-or ethynylene;
(R 52 ) p23 the benzene rings in the formula (PBM-21) are each optionally substituted with p 23R 52 Substituted, each R 52 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
each p23 is the same or different and each independently represents an integer of 0, 1, 2, 3 or 4;
ring D in formula (PBM-21) represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, (R) 53 ) p24 Represents the ring D optionally being substituted by p 24R 53 Substitution, each R 53 Identical or different and each independently represents an optionally substituted 5-to 15-membered heteroaryl, deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p24 represents an integer of 0, 1,2, or 3;
r in formula (PBM-22) 54 、R 55 、R 56 And R is 57 Wherein R is the same or different and each independently represents hydrogen, halogen, or hydroxy 54 、R 55 、R 56 And R is 57 When one of them represents a bond, the benzene ring or methylene group in the formula (PBM-22) to which the bond is attached is directly attached to R f ；
The symbol of the double bond in the formula (PBM-22)
Represents a bond that may be in a steric configuration (cis or trans, or E-or Z-configuration);
x in the formula (PBM-23) 13 represents-O-or-CH 2 -；
(R 58 ) p25 The 1,2,3, 4-tetrahydronaphthalene ring in the formula (PBM-23) is substituted with p 25R 58 Substituted, each R 58 The same or different and each independently represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p25 represents an integer of 1,2,3 or 4;
R 59 and R is 60 Wherein only one of them represents a bond and the other represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, where R is 59 And R is 60 When one of them represents a bond, the ring carbon atom in the formula (PBM-23) to which the bond is attached is directly attached to R f ；
Ring E in formula (PBM-24) represents a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S;
R 62 represents optionally substituted 5-to 15-membered heteroaryl, optionally substituted 5-to 15-membered heterocyclyl, deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
R 61 represents halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or deuterated C 1-6 An alkyl group;
r in formula (PBM-25) 63 Represents optionally substituted 5-to 15-membered heterocyclyl, deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
R 64 represents a 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, said heteroaryl group optionally being substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Substituents of alkoxy groups or any combination thereof;
(R 65 ) p26 the isoquinoline ring in the formula (PBM-26) is substituted with p 26R 65 Substituted, each R 65 The same or different and each independently represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C (O) NH 2 Deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p26 represents an integer of 1, 2, 3 or 4;
R 66 the same or different and each independently represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
x in formula (PBM-27) 14 Represents N or CR b23 Wherein R is b23 Represents hydrogen or halogen, X 15 Represents N or CH;
R 67 represents a bond, -C (O) NH-, or-NHC (O) -;
R 68 represents halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 69 represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl or-C 1-3 alkylene-C 3-6 Cycloalkyl;
R 70 represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group; or (b)
R 69 And R is 70 Together with the corresponding nitrogen and carbon atoms to which they are each attached form an optionally substituted 5-to 7-membered nitrogen containing heterocyclic ring;
R 71 represents hydrogen or a bond, R 72 Represents hydrogen or a bond, wherein R 71 And R is 72 Not both hydrogen and R 71 And R is 72 Wherein when R represents a bond and the other represents hydrogen 71 When the bond is represented, R is the same as 71 The ring carbon atoms to which they are attached being directly attached R f And when R 72 When the bond is represented, R is the same as 72 The ring carbon atoms to which they are attached being directly attached R f ；
R in formula (PBM-28) 74 Representing bond, C 1-3 Alkylene or halogenated C 1-3 An alkylene group;
R 73 represents optionally substituted C 3-6 Cycloalkyl, halo C 3-6 Cycloalkyl, or optionally substituted C 1-6 An alkyl group;
r in formula (PBM-29) 75 Represent C 1-3 Alkylene or halogenated C 1-3 An alkylene group;
R 76 represent C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, or optionally substituted C 3-6 Cycloalkyl;
r in formula (PBM-30) 77 Represent C 1-3 Alkylene or halogenated C 1-3 An alkylene group;
R 78 represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 79 and R is 80 Identical or different and each independently represents hydrogen, optionally substituted C 1-10 Alkyl or optionally substituted C 3-6 Cycloalkyl;
R 81 represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
x in the formula (PBM-31) 16 representing-S-or fragments
Wherein when X is 16 In the case of-S-, X is contained in the formula (PBM-31) 16 And heteroaryl of nitrogen atom is thiazolyl, and when X 16 Representing fragment->
When, in formula (PBM-31), X is contained 16 And heteroaryl of nitrogen atom is pyridinyl;
X 17 represents N or CH;
R 82 represents hydrogen or optionally substituted C 1-10 An alkyl group;
R 83 represents hydrogen, -C 1-3 Alkylene-optionally substituted 4-to 10-membered heterocyclyl, or optionally substituted 4-to 10-membered heterocyclyl;
R 84 represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-32) 85 And R is 86 Identical or different and each independently represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 87 representation-S (O) 2 NH 2 or-C (O) NH 2 ；
R in formula (PBM-33) 88 Represents hydrogen, hydroxy, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 89 represent C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group; or (b)
R 88 And R is 89 Together with the corresponding carbon and nitrogen atoms to which they are each attached form an optionally substituted 4-to 6-membered heteroaryl ring or an optionally substituted 4-to 6-membered heterocycle;
R 90 represents optionally substituted C 3-6 Cycloalkyl, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl or optionally substituted 4-to 10-membered heterocyclyl;
(R 91 ) p27 the pyridin-2 (1H) -one ring in formula (PBM-33) is substituted with p 27R 91 Substituted, each R 91 Identical or different and each independently represents hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p27 represents an integer of 1, 2 or 3;
ring F in formula (PBM-33) represents an arylene group or a 5-to 20-membered monocyclic or bicyclic heteroarylene group containing 1-4 heteroatoms selected from N, O and S; (R) 92 ) p28 Represents the ring F optionally being substituted by p 28R 92 Substitution, each R 92 Identical or different and each independently represents deuterium, halogen, hydroxy, cyano, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p28 represents an integer of 0, 1, 2, 3 or 4;
(R 93 ) p29 The benzene ring in the formula (PBM-34) is substituted with p 29R 93 Substituted, each R 93 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p29 represents an integer of 1, 2, 3, 4 or 5;
R 94 represents hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 95 represents NR b15 R b16 Wherein R is b15 、R b16 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl;
(PBM)X in-35) 18 、X 19 And X 20 Identical or different and each independently represents CH or N, wherein X 18 、X 19 And X 20 Not both N and X 18 、X 19 、X 20 And the six-membered ring of nitrogen atoms is optionally further substituted with 1 or 2 groups selected from halogen, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Substituents of alkyl groups or any combination thereof;
x in the formula (PBM-35) 21 And X 22 Identical or different and each independently represents C or N, wherein X 21 And X 22 Not both are N;
(R 96 ) p30 the benzene ring in the formula (PBM-35) is substituted with p 30R 96 Substituted, each R 96 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p30 represents an integer of 1, 2, 3, 4 or 5;
(R 97 ) p31 the tetrahydropyrrole ring in formula (PBM-35) is optionally substituted with p 31R 97 Substituted, each R 97 The same or different and each independently represents hydrogen, hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p31 represents an integer of 0, 1, 2, 3, 4, 5 or 6;
R 98 、R 99 、R 100 identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
x in the formula (PBM-36) 23 Represents CH or N;
R 101 represents a bond or-S-;
R 102 represents a bond or an optionally substituted 4-to 15-membered nitrogen-containing heterocyclic group;
R 103 represents a bond, halogen, amino, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenSubstitute C 1-6 Alkyl, or optionally substituted 4-to 15-membered nitrogen containing heterocyclyl;
wherein R is 102 And R is 103 Not both being bonds, and R 102 And R is 103 Wherein only one of R is a bond 102 When the bond is represented, R is the same as 102 The ring carbon atoms to which they are attached being directly attached R f And when R 103 When the bond is represented, R is the same as 103 The ring carbon atoms to which they are attached being directly attached R f ；
(R 104 ) p32 The six-membered ring in the formula (PBM-36) is optionally substituted with p 32R' s 104 Substituted, each R 104 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group; p32 represents an integer of 0, 1, 2, 3 or 4;
(R 105 ) p33 the benzene ring in the formula (PBM-37) is optionally substituted with p 33R 105 Substituted, each R 105 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p33 represents an integer of 1, 2, 3 or 4;
(R 106 ) p34 the phthalazinone ring in formula (PBM-37) is optionally substituted with p 34R 106 Substituted, each R 106 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p34 represents an integer of 0, 1, 2, 3 or 4;
(R 107 ) p35 the 2H-indazole ring in formula (PBM-38) is optionally substituted with p35 Rs 107 Substituted, each R 107 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p35 represents an integer of 0, 1, 2 or 3;
(R 108 ) p36 the benzene ring in the formula (PBM-38) is optionally substituted with p 36R 108 Substituted, each R 108 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p36 represents an integer of 0, 1, 2 or 3;
(R 109 ) p37 the 2H-indazole ring in formula (PBM-39) is optionally substituted with p 37R 109 Substituted, each R 109 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p37 represents an integer of 0, 1, 2 or 3;
(R 110 ) p38 the benzene ring in the formula (PBM-39) is optionally substituted with p 38R 110 Substituted, each R 110 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p38 represents an integer of 0, 1, 2 or 3;
(R 111 ) p39 the benzene ring in the formula (PBM-40) is optionally substituted with p 39R 111 Substituted, each R 111 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p39 represents an integer of 0, 1, 2, 3 or 4;
R 112 、R 113 、R 114 identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-41) 115 Represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 116 、R 117 、R 118 identical or different and each independently represents hydrogen, halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 119 ) p40 the benzene ring in the formula (PBM-41) is optionally substituted with p 40R 119 Substituted, each R 119 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p40 represents an integer of 0, 1, 2, 3 or 4;
r in formula (PBM-42) 120 、R 121 Identical or different and each independently represents hydrogen, halogen, C 1-3 Alkyl or halo C 1-3 An alkyl group;
R 122 represents bond, hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
R 123 the structure of the following formula is shown:
wherein R is 124 Represents a bond or hydrogen; (R) 125 ) p41 Represents the benzene ring optionally substituted by p 41R 125 Substituted, each R 125 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p41 represents an integer of 0, 1, 2, 3 or 4; or (b)
R 123 The structure of the following formula is shown:
wherein (R) 126 ) p42 Represents the benzene ring optionally substituted by p 42R 126 Substituted, eachR 126 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p42 represents an integer of 0, 1, 2, 3, 4 or 5;
wherein R is 122 And R is 124 Not both being bonds, and R 122 And R is 124 Wherein when R represents a bond 122 When the bond is represented, R is the same as 122 The ring nitrogen atom being bound directly to R f And when R 124 When the bond is represented, R is the same as 124 The ring carbon atoms to which they are attached being directly attached R f ；(R 127 ) p43 The benzene ring in the formula (PBM-43) is optionally substituted with p 43R 127 Substituted, each R 127 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p43 represents an integer of 0, 1, 2, 3 or 4;
r in formula (PBM-45) 131 Represent C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydrogen;
R 132 represent C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 4-to 8-membered nitrogen containing heterocyclyl or NR b17 R b18 Wherein R is b17 、R b18 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl or optionally substituted 4-to 8-membered heterocyclyl;
(R 133 ) p46 the benzene ring in the formula (PBM-45) is optionally substituted with p 46R 133 Substituted, each R 133 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p46 represents an integer of 0, 1, 2, 3 or 4;
(R 134 ) p47 the benzene ring in the formula (PBM-46) is optionally substituted with p 47R 134 Substituted, each R 134 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p47 represents an integer of 0, 1, 2, 3 or 4;
(R 135 ) p48 the benzene ring in the formula (PBM-46) is optionally substituted with p 48R 135 Substituted, each R 135 The same or different and each independently represents hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 An alkyl group;
p48 represents an integer of 0, 1, 2, 3 or 4;
ring H in formula (PBM-48) represents C 6-10 Arylene or C 5-10 Heteroarylene (R) 137 ) p49 Represents the ring H optionally being substituted by p 49R' s 137 Substitution, each R 137 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p49 represents an integer of 0, 1, 2, 3 or 4;
R 136 represents an optionally substituted 5-to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, optionally via a group selected from hydroxy, amino, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or halo C 1-6 Substituent substitution of alkyl;
x in formula (PBM-49) 24 、X 25 、X 26 Each independently represents CH or N;
R 138 represents-C (O) NHR b19 、-NHC(O)-R b19 、-S(O) 2 NHR b19 、-NHS(O) 2 R b19 、-S(O) 2 R b19 or-P (O) (R b19 ) 2 Wherein each R is b19 The same or differentAnd each independently represents C 1-6 Alkyl or deuterated C 1-6 An alkyl group;
R 139 and R is 140 Each independently represents halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 141 ) p50 represents the benzene ring optionally substituted by p 50R 141 Substitution, each R 141 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p50 represents an integer of 0, 1, 2,3 or 4; and
in the formula (PBM-50) (R) 143 ) p51 Represents the benzene ring optionally substituted by p 51R 143 Substitution, each R 143 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
p51 represents an integer of 0, 1, 2,3, 4 or 5;
R 142 representation H, C 1-6 Alkyl or halo C 1-6 An alkyl group;
(R 144 ) p52 the quinazoline ring in formula (PBM-50) is optionally substituted with p 52R 144 Substitution, each R 144 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p52 represents an integer of 1, 2, or 3;
r in formula (PBM-51) f2 Represents a bond, or R f2 represents-NH-R f3 -C (O) -, wherein the symbols represent the values associated with R f1 And R is f3 Represents optionally substituted C 3-8 Cycloalkyl;
(R 145 ) p53 1H-pyrrolo [2,3-b ] in the formula (PBM-51)]The pyridine ring is optionally substituted by p 53R 145 Substitution, each R 145 Each independently is cyano, halogen, hydroxy, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p53 represents an integer 0, 1, 2, 3, 4 or 5;
(R 146 ) p54 the pyridine ring in the formula (PBM-51) is optionally substituted with p 54R 146 Substitution, each R 146 Each independently is cyano, halogen, hydroxy, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy or NR b25 R b26 Wherein R is b25 、R b26 Identical or different and each independently represents hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl or optionally substituted 4-to 8-membered heterocyclyl, and p54 represents an integer 0, 1, 2 or 3; and
(R) in the formula (PBM-52) 147 ) p55 Represents the benzene ring optionally substituted by p 55R 147 Substitution, each R 147 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 Alkoxy, and p55 represents an integer 0, 1, 2, 3, 4 or 5;
R 148 represents NHC (O) or C (O) NH;
(R 149 ) p56 the 1H-pyrazole ring of formula (PBM-52) is optionally substituted with p 56R 149 Substitution, each R 149 Each independently is halogen, hydroxy, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy or halo C 1-6 Alkoxy, and p56 represents an integer of 0, 1 or 2; and
x in the formula (PBM-53) 27 Represents N or CH;
R 150 represents a bond or an optionally substituted methylene group (e.g., a halogen substituted methylene group);
ring I represents C 6-10 Arylene or 5 to 15 membered heteroarylene, (R) 151 ) p57 Represents the ring I optionally substituted by p 57R 151 Substitution, each R 151 Identical or different and are each independently deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p57 represents an integer of 0, 1, 2, 3 or 4;
(R 152 ) p58 the said compound of formula (PBM-53) contains X 27 Optionally p 58R' s 152 Substituted, each R 152 Each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p58 represents an integer of 0, 1 or 2;
(R 153 ) p59 the benzene ring in the formula (PBM-53) is optionally substituted with p 59R 153 Substituted, each R 153 Identical or different and each independently represents halogen, C 1-6 Alkoxy, C 1-6 Alkyl, deuterated C 1-6 Alkyl or halo C 1-6 Alkyl, and p15 represents an integer of 0, 1, 2, 3 or 4;
x in formula (PBM-54) 28 、X 29 And X 30 Each independently represents N or CH;
(R 154 ) p60 the naphthyl group in the formula (PBM-54) is optionally substituted with p 60R groups 154 Substituted, each R 154 Each independently represents halogen, hydroxy, amino, mercapto, nitro, cyano, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkyl or halo C 1-6 Alkyl, and p60 represents an integer of 0, 1, 2, 3, 4, 5, 6 or 7;
R 155 represents optionally substituted C 3-11 Cycloalkyl or optionally substituted 4-15 membered heterocontaining 1-4 heteroatoms selected from N, O and SA cyclic group;
R 156 represents hydrogen, halogen, hydroxy, cyano, amino, mercapto, nitro, C 2-6 Alkynyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkyl or halo C 1-6 An alkyl group;
r in formula (PBM-55) 157 Represent C 6-10 Aryl, or heteroaryl comprising 1 or 2 5-to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 The aryl and the heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
R 158 represents a 5-to 15-membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, wherein the 5-to 15-membered heteroaryl group is optionally substituted with one or more substituents selected from: halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 An alkoxy group;
(R 159 ) p61 the isoindolinone ring in formula (PBM-55) is substituted with p 61R 159 Substituted, each R 159 The radicals are identical or different and each independently represents halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p61 represents an integer of 0, 1, 2 or 3;
x in formula (PBM-56) 31 Represents N or CH;
(R 160 ) p62 x-containing in the formula (PBM-56) 31 Is substituted by p 62R 160 Substituted, each R 160 The radicals are identical or different and each independently represents halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, or halogenSubstitute C 1-6 Alkoxy, and p62 represents an integer of 0, 1, 2, 3 or 4; and
ring J represents a 5-to 15-membered heteroarylene group, (R) 161 ) p63 Represents the ring J optionally substituted by p 63R 161 Substituted, each R 161 The radicals are identical or different and each independently represents halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, or halo C 1-6 Alkoxy, and p63 represents an integer of 0, 1, 2, or 3.
15. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to claim 12 wherein the PBM represents the structure of the formula:
16. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in claim 12 wherein
The R is f Represents a bond, -O-, -NHC (O) -, -C (O) NH-, or-NH-, or
R f The structure of the following formula is shown:
-N(R g )-、-NHC(O)-C 1-6 alkylene group-W 5 -*、-NHC(O)-C 2-6 alkenylene-W 5 -*、-C(O)NH-C 1-6 Alkylene group-W 5 -*、-C(O)NH-C 2-6 alkenylene-W 5 -*、-NHC(O)-W 5 -*、-C(O)NH-W 5 -*、-O-C 1-6 Alkylene group-W 5 -*、-O-C 2-6 alkenylene-W 5 -*、-O-W 5 -*、-O-C 1-6 alkylene-N (R) i )-*、-O-C 2-6 alkenylene-N (R) i )-*、-N(R g )-C 1-6 alkylene-N (R) i )-*、-N(R g )-C 2-6 alkenylene-N (R) i )-*、-W 5 -、-W 5 -N(R g )-*、-N(R g )-W 5 -*、-N(R g )-W 5 -N(R i )-*、-C 1-6 Alkylene group-W 5 -*、-C 2-6 alkenylene-W 5 -*、-C 1-6 alkylene-C (O) -W 5 -*、-C 2-6 alkenylene-C (O) -W 5 -*、-C(O)-W 5 -*、-C 1-6 alkylene-C (O) NH-C 1-6 Alkylene group-W 5 -*、-C 1-6 alkylene-C (O) NH-C 2-6 alkenylene-W 5 -*、-C 2-6 alkenylene-C (O) NH-C 1-6 Alkylene group-W 5 -*、-C 2-6 alkenylene-C (O) NH-C 2-6 alkenylene-W 5 -*、-C 1-6 alkylene-NHC (O) -C 1-6 Alkylene group-W 5 -*、-C 1-6 alkylene-NHC (O) -C 2-6 alkenylene-W 5 -*、-C 2-6 alkenylene-NHC (O) -C 1-6 Alkylene group-W 5 -*、-C 2-6 alkenylene-NHC (O) -C 2-6 alkenylene-W 5 -*、-C 1-6 alkylene-C (O) NH-, -C 2-6 alkenylene-C (O) NH-, -C 1-6 alkylene-NHC (O) -, -C 2-6 alkenylene-NHC (O) -, -C 1-6 Alkylene-, -C 2-6 Alkenylene-, -C 1-6 alkylene-N (R) i )-*、-C 2-6 alkenylene-N (R) i )-*、
Wherein R is g And R is i Each independently represents hydrogen or C 1-6 Alkyl, and the C 1-6 Alkylene and said C 2-6 Alkenylene is optionally substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Substituents of alkoxy groups or any combination thereof;
wherein the radical W 5 The structure of the following formula is shown:
wherein each ring W 6 Identical or different and each independently represents a nitrogen-containing heterocyclylene group, t1 represents an integer 1 or 2, (R) a2 ) m2 Representing each ring W 6 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and the C 1-6 Alkylene and said C 2-6 Alkenylene is optionally substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 An alkoxy group or any combination thereof, and m2 represents an integer of 0 to 20;
each ring W 7 Identical or different and each independently represents a nitrogen-containing heterocyclylene, arylene, or heteroarylene group, t2 represents an integer 0 or 1, (R) a3 ) m3 Representing each ring W 7 Independently optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m3 represents an integer of 0 to 20; and
the symbol x represents the connection point to LIN.
17. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to claim 12 wherein R f representation-W 7 -R h -W 5 Wherein R is h Represents optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene group, W 5 And W is 7 As defined in claim 12 or 16.
18. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in any one of claims 12 or 16 to 17 wherein W is 5 The structure of the following formula is shown:
Wherein each ring W 6 Identical or different and each independently represents4-to 20-membered nitrogen-containing heterocycles, e.g.
Piperidylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene, diazepanylene, azepanylene, azacyclooctylene, diazepanylene, azabicyclo [3.1.1] heptylene, azabicyclo [2.2.1] heptylene, azabicyclo [2.2.2] octanylene, diazabicyclo [3.1.1] heptanylene, diazabicyclo [2.2.1] octanylene, diazabicyclo [3.2.1] octanylene, diazabicyclo [2.2.2] octanylene, 3-azaspiro [5.5] undecylene, 8-azaspiro [4.5] decane, 2-oxa-8-azaspiro [4.5] decane, methyl-decane, or 3-oxa-8-spiro [4.5] decane
t1 represents an integer of 1 or 2, (R) a2 ) m2 Representing each ring W 6 Optionally by m 2R a2 Substituted by radicals, each R a2 C independently being deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 12a -R 11a -, wherein R is 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and the C 1-6 Alkylene and said C 2-6 Alkenylene is optionally substituted with one or more groups selected from halogen, hydroxy, mercapto, cyano, amino, nitro, C 1-6 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 An alkoxy group or any combination thereof, and m2 represents an integer of 0 to 20;
each ring W 7 The same or different and each independently represents a 4-to 15-membered nitrogen-containing heterocyclylene group, a 6-to 10-membered arylene group, or a 5-to 10-membered heteroarylene group, for example,
piperidylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azepanylene, diazepanylene, azepanylene, azacyclooctylene, diazepanylene, azabicyclo [3.1.1] heptanylene, azabicyclo [2.2.1] heptanylene, azabicyclo [ 2.2.2.2 ] octanylene, azabicyclo [2.2.2] octanylene, diazabicyclo [3.1.1] heptanylene, diazabicyclo [2.2.1] heptanylene, diazabicyclo [3.2.1] octanylene, diazabicyclo [2.2.2] octanylene, 3-azaspiro [5.5] undecylene, 8-azaspiro [4.5] decane, 2-oxa-8-azaspiro [4.5] decane, methyl-2-oxaspiro [ 4-decane ] octanylene phenylene, naphthylene, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thiophenylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothiophenylene, indazolyl, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo [2,1,3] oxadiazolylene, benzo [2,1,3] thiadiazolylene, benzo [1,2,3] thiadiazolylene, quinolinylene, isoquinolinyl, naphthyridine, cinnolinyl, quinazoline, quinoxalinylene, phthalazinyl, pyrazolo [1,5-a ] pyridine subunit, pyrazolo [1,5-a ] pyrimidine subunit, imidazo [1,2-a ] pyridine subunit, 1H-pyrrolo [3,2-b ] pyridine subunit, 1H-pyrrolo [2,3-b ] pyridine subunit, pyrrolo [2,1-b ] thiazole subunit, or imidazo [2,1-b ] thiazole subunit, or
t2 represents an integer of 0 or 1, (R) a3 ) m3 Representing each ring W 7 Independently optionally by m 3R a3 Substituted by radicals, each R a3 C independently being deuterium, optionally deuterated 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or R 16a -R 15a -, wherein R is 15a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 16a Represents halogen, R 17a R 18a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 17a And R is 18a Identical or different and each independently represents hydrogen or C 1-3 Alkyl, and m3 represents an integer of 0 to 20; and
the symbol x represents the connection point to LIN.
19. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in claim 16 or 17 wherein W is 5 The following groups are represented:
wherein said groups are optionally further substituted with one or more C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, R 12a -R 11a -or any combination thereof, wherein R 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; and
the symbol x represents the connection point to LIN.
20. A compound of formula (III) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in any one of claims 12 or 16 to 17 wherein R f The following groups are represented:
bond, -O-, -NHC (O) -, -C (O) NH-, -N (CH) 3 )-、-N(CH 3 )-(CH 2 ) 2 -N(CH 3 )-*、-N(CH 3 )-(CH 2 ) 3 -N(CH 3 )-*、-NH-(CH 2 ) 2 -N(CH 3 )-*、-N(CH 3 )-(CH 2 ) 3 -NH-*、-CH 2 -NHC(O)-*、-CH 2 -C(O)NH-*、-CH 2 -NH-*、-O-(CH 2 ) 2 -N(CH 3 )-*、-O-(CH 2 ) 2 -NH-, or-CH 2 -N(CH 3 ) -, or
Wherein said groups are optionally further substituted with one or more C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, R 12a -R 11a -or any combination thereof, wherein R 11a Is optionally substituted C 1-6 Alkylene or optionally substituted C 2-6 Alkenylene, R 12a Represents halogen, R 13a R 14a N-, hydroxy, carboxy, ethynyl, or vinyl, wherein R 13a And R is 14a Identical or different and each independently represents hydrogen or C 1-3 An alkyl group; and
The symbol x represents the connection point to LIN.
21. The compound of formula (II), or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof, of claim 12, wherein ULM represents the structure of formula (ULM-1), formula (ULM-2), formula (ULM-3), formula (ULM-4), formula (ULM-5), formula (ULM-6), formula (ULM-7), formula (ULM-8), formula (ULM-9), formula (ULM-10), formula (ULM-11), or formula (ULM-12) below.
Wherein the method comprises the steps of
A represents CO or CH 2 Or CD (compact disc) 2 ；
R 1 、R 2 、R 3 And R is 4 Identical or different and each independently represents hydrogen, deuterium, halogen, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, or halo C 1-6 An alkyl group;
(R b ) n represents the benzene ring optionally substituted by n R b Substituted, each R b Identical or different and each independently represents deuterium, halogen, hydroxy, mercapto, nitro, amino, cyano, optionally deuterated C 1-6 Alkyl, optionally deuterated C 1-6 Alkoxy, halo C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl; and
n represents an integer of 0, 1, 2 or 3.
22. The compound of formula (II), or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof, of claim 20, wherein ULM represents the structure of formula (ULM-13), formula (ULM-14), formula (ULM-15), formula (ULM-16), formula (ULM-17), formula (ULM-18), formula (ULM-19), formula (ULM-20), formula (ULM-21), formula (ULM-22), formula (ULM-23), or formula (ULM-24) below.
Wherein said A, (R) b ) n 、R b As defined in claim 19.
23. A compound of formula (III) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to claim 20 wherein the ULM represents the structure of the formula:
24. the compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof of any one of claims 12-22, wherein LIN represents the structure of the formula:
wherein R is 5 And R is 6 Identical or different and each independently represents:
hydrogen, fluorine, chlorine, bromine, iodine, optionally substituted methyl, or optionally substituted straight or branched C 2-30 An alkyl group, a hydroxyl group,
wherein said straight or branched C 2-30 The main carbon chain of the alkyl group optionally having one or more groups R inserted therein c And/or one or more radicals R d Or one or more radicals R c And R is R d Any combination of said groups R c 、R d Or a group R c And R is R d In combination, breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R c Selected from O, N (R) e )、C(O)、C(O)O、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、OC(O)、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 Alkyl, and when said straight or branched chain C 2-30 The main carbon chain of the alkyl is inserted with more than two groups R c When the radicals R are c Are not directly connected with each other; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof; and
hydrogen of the methyl group and the C 2-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected fromReplacement: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof.
25. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in any one of claims 12 to 22 wherein R 5 And R is 6 The same or different and each independently represents hydrogen, fluorine, chlorine, bromine or iodine, or represents a structure of the formula:
-C 1-30 an alkyl group;
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -(R c -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -(R d -(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(R c -R d -(C(R a6 )(R a7 )) n2 ) m4 -CH 3 ；
-(C(R a4 )(R a5 )) n1 -(R c -(C(R a6 )(R a7 )) n2 ) m4 -(R d -(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(R d -R c -(C(R a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 -(R d -(C(R a6 )(R a7 )) n2 ) m4 -(R c -(C(R a8 )(R a9 )) n3 ) m5 -H；
Wherein each group R c Selected from O, N (R) e )、C(O)、C(O)O、OC(O)、S(O)、S(O) 2 、S(O) 2 NH、NHS(O) 2 、C(O)N(R e )、N(R e ) C (O), or N (R) e )C(O)N(R e ) Wherein each R is e Independently represent H or C 1-6 An alkyl group; each group R d Selected from cycloalkylene radicals (e.g. C 3-20 Cycloalkylene), arylene (e.g. C 3-20 Arylene), heterocyclylene (e.g., 4-to 20-membered heterocyclylene), heteroarylene (e.g., 4-to 20-membered heteroarylene), alkynylene (e.g., C 2-6 Alkynylene), alkenylene (e.g. C 2-6 Alkenylene) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene are each independently of the other optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, ammoniaRadicals, mercapto radicals, halogen radicals, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof;
the C is 1-30 One or more CH's of alkyl groups 2 Optionally further substituted with a substituent selected from the group consisting of: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, or optionally deuterated C 1-6 alkyl-C (O) NH-; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
26. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to claim 12 wherein R 5 And R is 6 The structures of the following formulae are identical or different and are each independently represented:
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(O-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(N(R e )-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(C(O)N(R e )-(C(R a8 )(R a9 )) n3 ) m5 -(C(O)N(R e )-
(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -(C(O)N(R e )-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -C(O)N(R e )-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 -(N(R e )C(O)-(C(R a6 )(R a7 )) n2 ) m4 -(O-(C(R a8 )(R a9 )) n3 ) m5 -(O-(C(R a10 )(R a11 )) n4 ) m6 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)-(C(R a6 )(R a7 )) n2 -(O-(C(R a8 )(R a9 )) n3 ) m4 -H；
-(C(R a4 )(R a5 )) n1 -N(R e )C(O)N(R e )-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 -C(O)-(C(R a6 )(R a7 )) n2 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (arylene- (C (R) a6 )(R a7 )) n2 ) m4 Arylene- (C (R) a8 )(R a9 )) n3 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heterocyclylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heterocyclylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 -H；
-(C(R a4 )(R a5 )) n1 - (heteroarylene- (C (R) a6 )(R a7 )) n2 ) m4 - (heteroarylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 -H; or (b)
-(C(R a4 )(R a5 )) n1 - (cycloalkylene- (C (R) a6 )(R a7 )) n2 ) m4 - (cycloalkylene- (C (R) a8 )(R a9 )) n3 ) m5 -H；
Wherein each R e Independently represent H or C 1-6 An alkyl group;
the cycloalkylene, the arylene, the heterocyclylene and the heteroarylene are each independently optionally further substituted with C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereofSubstitution of a substituent;
R a4 、R a5 、R a6 、R a7 、R a8 、R a9 、R a10 and R is a11 Each independently represents H, deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, or optionally deuterated C 1-6 alkyl-C (O) NH-; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
27. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to claim 12 wherein R 5 And R is 6 The same or different and each independently represents the following group:
H. fluorine, chlorine, bromine, iodine, -CH 3 、-CH 2 -CH 3 、-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -CH 3 、-(CH 2 ) 7 -CH 3 、-(CH 2 ) 8 -CH 3 、-(CH 2 ) 9 -CH 3 、-(CH 2 ) 10 -CH 3 、-(CH 2 ) 11 -CH 3 、-(CH 2 ) 12 -CH 3 、-(CH 2 ) 13 -CH 3 、-(CH 2 ) 14 -CH 3 、-(CH 2 ) 15 -CH 3 、-(CH 2 ) 16 -CH 3 、-(CH 2 ) 17 -CH 3 、-(CH 2 ) 18 -CH 3 、-(CH 2 ) 19 -CH 3 、-(CH 2 ) 20 -CH 3 、-(CH 2 ) 21 -CH 3 、-(CH 2 ) 22 -CH 3 、-(CH 2 ) 25 -CH 3 、-(CH 2 ) 29 -CH 3 ；-CH 2 -O-CH 3 、-CH 2 -O-CH 2 -CH 3 、-CH 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 1 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 11 -CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 12 -CH 3 、-(CH 2 ) 3 -O-CH 3 、-(CH 2 ) 3 -O-CH 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 7 -CH 3 、-(CH 2 ) 4 -O-CH 3 、-(CH 2 ) 4 -O-CH 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 4 -O-(CH 2 ) 6 -CH 3 、-(CH 2 ) 5 -O-CH 3 、-(CH 2 ) 5 -O-CH 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 5 -O-(CH 2 ) 5 -CH 3 、-(CH 2 ) 6 -O-CH 3 、-(CH 2 ) 6 -O-CH 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 6 -O-(CH 2 ) 4 -CH 3 、-(CH 2 ) 7 -O-CH 3 、-(CH 2 ) 7 -O-CH 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -O-(CH 2 ) 3 -CH 3 、-(CH 2 ) 8 -O-CH 3 、-(CH 2 ) 8 -O-CH 2 -CH 3 、-(CH 2 ) 8 -O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-CH 3 、-CH(CH 3 )-O-CH 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 9 -CH 3 、-CH(CH 3 )-O-(CH 2 ) 10 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 1 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 6 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 7 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 8 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 9 -OCH 3 、-CH 2 -(O(CH 2 ) 2 ) 10 -OCH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 1 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 2 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 3 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 4 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 5 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 6 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 7 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 8 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 9 -OCH 2 CH 3 、-(CH 2 ) 4 -(O(CH 2 ) 2 ) 10 -OCH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 9 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 10 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 6 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 7 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 8 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -CH 3 、-CH 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-CH 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 2 -(O(CH 2 ) 3 ) 1 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 3 -(O(CH 2 ) 3 ) 2 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 4 -(O(CH 2 ) 3 ) 3 -OCH 2 CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 2 ) 5 -(O(CH 2 ) 3 ) 4 -OCH 2 CH 2 CH 3 、-CH 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-CH 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-(CH 2 ) 3 -O-(CH 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 2 -(O(CH 2 ) 2 ) 1 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 3 -(O(CH 2 ) 2 ) 2 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 4 -(O(CH 2 ) 2 ) 3 -O-CH 2 CH 3 、-(CH 2 ) 3 -(O(CH 2 ) 3 ) 5 -(O(CH 2 ) 2 ) 4 -O-CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -O-(CH 2 ) 2 -O-CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 3 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 2 -(O(CH 2 ) 2 ) 4 -O-(CH 2 ) 2 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 4 CH 3 、-(CH 2 ) 5 -(O(CH 2 ) 2 ) 2 -O-(CH 2 ) 5 CH 3 、-(CH 2 ) 1 -N(R e )-CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 1 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 8 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 10 -CH 3 、-(CH 2 ) 2 -N(R e )-(CH 2 ) 11 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 3 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 -N(R e )-(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 6 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 7 -N(R e )-(CH 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 1 -CH 3 、-(CH 2 ) 8 -N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 1 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 2 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 3 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 4 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 5 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 6 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 7 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 8 -CH 3 、-CH(CH 3 )-N(R e )-(CH 2 ) 9 -CH 3 、-CH 2 C(O)NHCH 3 、-(CH 2 ) 2 C(O)NHCH 2 CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 C(O)NH(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 C(O)NH(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 C(O)NH(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 C(O)NH(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 C(O)NH(CH 2 ) 7 -CH 3 、U-(CH 2 ) 9 C(O)NH(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 C(O)NH(CH 2 ) 9 -CH 3 、-(CH 2 ) 2 C(O)NH(CH 2 ) 2 -O-CH 2 -CH 3 、-CH 2 NHC(O)CH 3 、-(CH 2 ) 2 NHC(O)CH 2 CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 2 -CH 3 、-(CH 2 ) 3 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 3 -CH 3 、-(CH 2 ) 5 NHC(O)(CH 2 ) 4 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 6 NHC(O)(CH 2 ) 5 -CH 3 、-(CH 2 ) 7 NHC(O)(CH 2 ) 6 -CH 3 、-(CH 2 ) 8 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 9 NHC(O)(CH 2 ) 8 -CH 3 、-(CH 2 ) 10 NHC(O)(CH 2 ) 9 -CH 3 、-(CH 2 ) 4 NHC(O)(CH 2 ) 7 -CH 3 、-(CH 2 ) 2 NHC(O)(CH 2 ) 2 -O-CH 2 -CH 3 、-(CH 2 ) 4 NHC(O)CH 3 、-CH 2 -piperidinyl-CH 3 、-CH 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperidinyl-CH 3 、-(CH 2 ) 3 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperidinyl-CH 3 、-(CH 2 ) 4 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperidinyl-CH 3 、-(CH 2 ) 5 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperidinyl-CH 3 、-(CH 2 ) 6 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperidinyl-CH 3 、-(CH 2 ) 7 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperidinyl-CH 3 、-(CH 2 ) 8 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl-CH 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-CH 2 -N(R e )-(CH 2 ) 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl-CH 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 8 -N(R e )-CH 2 -piperidinyl- (CH) 2 ) 7 -CH 3 、-CH 2 -piperazinylene-CH 3 、-CH 2 -piperazinylene-CH 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-CH 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 2 -piperazinylene-CH 3 、-(CH 2 ) 2 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 2 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 3 -piperazinylene-CH 3 、-(CH 2 ) 3 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 3 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 4 -piperazinylene-CH 3 、-(CH 2 ) 4 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 4 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 5 -piperazinylene-CH 3 、-(CH 2 ) 5 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 5 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 6 -piperazinylene-CH 3 、-(CH 2 ) 6 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 6 -CH 3 、-(CH 2 ) 6 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 7 -piperazinylene-CH 3 、-(CH 2 ) 7 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 7 -piperazinylene- (CH) 2 ) 7 -CH 3 、-(CH 2 ) 8 -piperazinylene-CH 3 、-(CH 2 ) 8 -piperazinylene-CH 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 2 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 3 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 4 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 5 -CH 3 、-(CH 2 ) 8 -piperazinylene- (CH) 2 ) 6 -CH 3 Or- (CH) 2 ) 8 -piperazinylene- (CH) 2 ) 7 -CH 3 ；
Wherein said piperidinyl and said piperazinyl independently of each other are optionally further substituted with a C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, hydroxy, amino, mercapto, nitro, halogen, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, halo-C 1-6 Alkyl, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, cyano-, or any combination thereof;
CH in said group 3 Hydrogen and one or more CH 2 Optionally further substituted with a substituent selected from the group consisting ofAnd (3) substitution: deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 Alkylene, optionally deuterated C 1-6 alkyl-NHC (O) -, optionally deuterated C 1-6 alkyl-C (O) NH-, or any combination thereof;
each R is e Independently represent H or C 1-6 An alkyl group; and
n1, n2, n3, n4, m5, m6 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
28. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof as claimed in any one of claims 12 to 27 wherein said-R f -LIN-represents the following group:
-CH 2 -、-O-CH 2 -**、-NHC(O)-CH 2 -**、-C(O)NH-CH 2 -**、-NH-CH 2 -**、-N(CH 3 )-CH 2 -**、
-N(CH 3 )-(CH 2 ) 2 -N(CH 3 )-CH 2 -**、-N(CH 3 )-(CH 2 ) 3 -N(CH 3 )-CH 2 -**、-NH-(CH 2 ) 2 -N(CH 3 )-CH 2 -**、
-N(CH 3 )-(CH 2 ) 3 -NH-CH 2 -**、-CH 2 -NHC(O)-CH 2 -**、-CH 2 -C(O)NH-CH 2 -**、-CH 2 -NH-CH 2 -**、
-O-(CH 2 ) 2 -N(CH 3 )-CH 2 -**、-O-(CH 2 ) 2 -NH-CH 2 -, x or-CH 2 -N(CH 3 )-CH 2 -, or
Wherein said groups are optionally further substituted with one or more C selected from deuterium, optionally deuterated 1-6 Alkyl, optionally halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, halogen, amino, hydroxy, mercapto, cyano, carboxyl, C 2-6 Alkynyl, C 2-6 Alkenyl, optionally deuterated C 3-6 Cycloalkyl, or any combination thereof; and
the symbol denotes the point of attachment to the ULM.
29. The compound of formula (II), or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug, or polymorph thereof, of claim 12, which is also represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II-14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21), formula (II-22), formula (II-23), formula (II-24), formula (II-25), formula (II-26), formula (II-27), formula (II-28), formula (II-29), formula (II-30), formula (II-31), formula (II-33), formula (II-35), formula (II-33, formula (II-36), formula (II-37), formula (II-38), formula (II-39), formula (II-40), formula (II-41), formula (II-42), formula (II-43), formula (II-44), formula (II-45), formula (II-46), formula (II-47), formula (II-48), formula (II-49), formula (II-50), formula (II-51), formula (II-52), formula (II-53), formula (II-55), formula (II-56), formula (II-57), formula (II-58), formula (II-59), formula (II-60), formula (II-61), formula (II-62), formula (II-63), formula (II-64), formula (II-65), or formula (II-66).
Therein, A, R 1 、R 2 、R 3 、R 4 、(R b ) n 、LIN、R f 、(R 1 ) p1 、(R 2 ) p2 、(R 4 ) p3 、(R 5 ) p4 、(R 7 ) p5 、R 8 、(R 9 ) p6 、R 10 、(R 11 ) p7 、R 12 、R 13 、R 14 Ring A, ring B, ring C, R 15 、(R 16 ) p9 、X 1 、X 2 、X 3 、(R 20 ) p10 、R 21 、R 22 、(R 23 ) p11 、(R 24 ) p12 、R 25 、X 4 、X 5 、X 6 、X 7 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、(R 34 ) p13 、R 35 、(R 36 ) p14 、R 37 、X 8 、X 9 、X 10 、X 11 、X 12 、R 38 、R 39 、(R 40 ) p15 、(R 42 ) p16 、(R 43 ) p17 、(R 44 ) p18 、(R 45 ) p19 、(R 46 ) p20 、(R 48 ) p21 、(R 49 ) p22 、R 50 、R 51 、(R 52 ) p23 、(R 53 ) p24 、R 54 、R 55 、R 56 、R 57 、(R 58 ) p25 、X 13 、R 59 、R 60 、R 61 、R 62 、R 63 、R 64 、(R 65 ) p26 、R 66 、R 67 、R 68 、R 69 、R 70 、X 14 、X 15 、R 73 、R 74 、R 75 、R 76 、R 77 、R 78 、R 79 、R 80 、R 81 、X 16 、X 17 、R 82 、R 83 、R 84 、R 85 、R 86 、R 87 、R 88 、R 89 、R 90 、(R 91 ) p27 、(R 92 ) p28 、(R 93 ) p29 、R 94 、R 95 、(R 96 ) p30 、(R 97 ) p31 、X 18 、X 19 、X 20 、X 21 、X 22 、R 98 、R 99 、R 100 、R 101 、R 102 、R 103 、X 23 、(R 104 ) p32 、(R 105 ) p33 、(R 106 ) p34 、(R 107 ) p35 、(R 108 ) p36 、(R 109 ) p37 、(R 110 ) p38 、(R 111 ) p39 、R 112 、R 113 、R 114 、R 115 、R 116 、R 117 、R 118 、(R 119 ) p40 、R 120 、R 121 、R 122 、R 123 、(R 125 ) p41 、(R 127 ) p43 、R 131 、R 132 、(R 133 ) p46 、(R 134 ) p47 、(R 135 ) p48 、R 136 、(R 137 ) p49 、X 24 、X 25 、X 26 、R 138 、R 139 、R 140 、(R 141 ) p50 、R 142 、(R 143 ) p51 、(R 144 ) p52 、(R 145 ) p53 、(R 146 ) p54 、R f2 、(R 147 ) p55 、R 148 、(R 149 ) p56 、X 27 Ring I, R 150 、(R 151 ) p57 、(R 152 ) p58 、(R 153 ) p59 、X 28 、X 29 、X 30 、(R 154 ) p60 、R 155 、R 156 、R 157 、R 158 、(R 159 ) p61 、X 31 、(R 160 ) p62 Rings J and (R) 161 ) p63 As defined in claim 13.
30. A compound of formula (II) as defined in claim 12, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof, selected from:
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
N- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindol-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindol-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindol-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-3-oxoisoindolin-5-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-3-oxoisoindolin-5-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-3-oxoisoindolin-5-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -5-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(S) -3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(S) -3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(S) -3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(S) -3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
3- (5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
3- (5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-6-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-6-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-6-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuranyl-3-yl) oxy) quinazolin-6-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
3- (1-oxo-5- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-1-oxo-5- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-1-oxo-5- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-1-oxo-5- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-5- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-1-oxo-5- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-1-oxo-5- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-1-oxo-5- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methoxy) phenyl) acetamide;
N- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methoxy) phenyl) acetamide;
n- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methoxy) phenyl) acetamide;
n- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methoxy) phenyl) acetamide;
3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
N- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
N- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
3- (5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepino [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin) o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin) o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin) o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
3- (5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -1-oxoisoindol-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -5-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
n- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxo-isoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxo-isoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxo-isoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -3-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-3-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-3-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-3-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
3- (5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl) ]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
N- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindol-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindol-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindol-5-yl) methyl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (2-chloro-3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindol-5-yl) methyl) piperidin-4-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (tert-butyl) -N- (4- (5- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -1,2, 4-oxadiazole-5-carboxamide;
5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
(S) -5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
(S) -5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
(S) -5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
(S) -6- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3R, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((3R, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3R, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((3R, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((3 s,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3 r,4 r) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((3R, 4R) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3 s,4 s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((3S, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3-fluoropiperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (4- (1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (4-chloro-1- (4-hydroxyphenyl) -2-phenylbut-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((2- (4- (4-chloro-1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -6- (((2- (4- (1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((2- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((((3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
6- ((((3S, 4S) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-aminopyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -3-chloropyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
6- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) nicotinamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazine-3-carboxamide;
5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((5-methoxy-4- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2-nitrophenyl) amino) methyl) isoindoline-1, 3-dione;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
n- (2- ((2- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) phenyl) acrylamide;
5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (3- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) propyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
n- (4- ((3-chloro-4-fluorophenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) quinazolin-6-yl) acrylamide;
5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- ((4- ((3, 4-dichloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((4- ((3-chloro-4-fluorophenyl) amino) -7- (((S) -tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((4- ((3-chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) oxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) but-2-enamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (7- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (2, 6-Dioxopiperidin-3-yl) -5- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-5- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-6- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -5-fluoro-6- ((4- (((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -5- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-5- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -5-fluoro-6- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -4-fluoro-6- ((4- ((R, E) -1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazolyl-2 (2, 4) -pyridinyl-1 (4, 5) -pyrazolyl heterocyclylundecano-5 6 -yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -1'- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) - [1,4' -bipiperidin ] -4-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
n- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) -4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazine-1-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
4- (2, 6-dichlorobenzoylamino) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazole-3-carboxamide;
N- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) -1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidine-4-carboxamide;
n- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methoxy) phenyl) acetamide;
n- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methoxy) phenyl) acetamide;
n- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methoxy) phenyl) acetamide;
N- (5-cyclobutyl-1H-pyrazol-3-yl) -2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methoxy) phenyl) acetamide;
5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
3- ((4- (2- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
N- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
N- (2-chloro-6-methylphenyl) -2- ((6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
n- (2-chloro-6-methylphenyl) -2- ((6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- (3- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) propoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
4- ((2, 4-dichloro-5-methoxyphenyl) amino) -7- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methoxy) -6-methoxyquinoline-3-carbonitrile;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepino [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin-o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin-o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin-o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- ((2-fluoro-5- ((8 s,9 r) -5-fluoro-9- (1-methyl-1H-1, 2, 4-triazol-5-yl) -3-oxo-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de ] phthalazin-8-yl) phenyl) ethynyl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphino) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphono) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (6-amino-5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (4- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -5-isopropoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
(4R)-2 6 -amino-1 1 - (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -5 5 -fluoro-4, 7-dimethyl-6-oxo-1 1 H-3-oxa-7-aza-2 (3, 5) -pyrido-1 (4, 3) -pyrazolo-5 (1, 2) -benzoheterocyclo octatomato-1 5 -carbonitrile;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) -N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) acetamide;
5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) acetyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (2- ((S) -4- (4-chlorophenyl) -2,3, 9-trimethyl-6H-thieno [3,2-f ] [1,2,4] triazolo [4,3-a ] [1,4] diazepin-6-yl) ethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (5- ((R) -2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazol-3-yl) benzamide;
n- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridazin-3-yl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
N- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
n- (tert-butyl) -3- ((2- ((4- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethoxy) phenyl) amino) -5-methylpyrimidin-4-yl) amino) benzenesulfonamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
N- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
n- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -5-fluoro-6- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-6- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- (((1- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
5- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -6-fluoroisoindoline-1, 3-dione;
6- ((4- (4- (6- (5- ((R) -2- (2, 4-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenylyl) biphenyl)]-2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) benzeneGroup) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (6- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (3- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1R, 4R) -5- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylthio) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (5- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- (((2R) -4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
2- (4- ((((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) methyl) phenyl) -5-fluorobenzofuran-7-carboxamide;
n- (2- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
5- ((4- (1- (4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-yl) ethyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
n- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2-chlorophenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (3- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-chlorophenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (3- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-chlorophenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) methyl) piperidin-4-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -6-oxo-decahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((3- ((3 ar,4s,9 br) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3a,4,5,9 b-hexahydro-1H-pyrrolo [3,2-c ] quinolin-8-yl) phenyl) amino) methyl) isoindoline-1, 3-dione;
6- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
n- (4- (5- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -3- (tert-butyl) -1,2, 4-oxadiazole-5-carboxamide;
n- (4- (5- (4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -3- (tert-butyl) -1,2, 4-oxadiazole-5-carboxamide;
N- (4- (5- (4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -3- (tert-butyl) -1,2, 4-oxadiazole-5-carboxamide;
4-bromo-6- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -6-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -6-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -6-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -6-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- (4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) pyridazine-3-carboxamide;
6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) nicotinamide;
6- (8- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-3-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (6- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (3- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
4-bromo-5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (7- (((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
4-bromo-5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) piperidine-4-carboxamide;
1'- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) - [1,4' -bipiperidin ] -4-carboxamide;
4- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) piperazine-1-carboxamide;
N- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (2, 6-dichlorobenzoylamino) -1H-pyrazole-3-carboxamide;
1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -N- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) piperidine-4-carboxamide;
2- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methoxy) phenyl) -N- (5-cyclobutyl-1H-pyrazol-3-yl) acetamide;
4-bromo-5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- (((4- (2- ((1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) -5-chloropyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((2 ' - ((1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) -5' -chloro- [2,4' -bipyridin ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
3- ((4- (2- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
2- ((6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide;
2- ((6- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide;
2- ((6- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide;
4- ((4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
n- (4- ((4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- (4- (((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
2- (4- ((3S) -1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- ((3S) -1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin-o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) isoindoline-1, 3-dione;
2- ((5- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
2- ((5- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
2- ((5- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-1-yl) pyridin-2-yl) amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5-bromo-6- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -6-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
6- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -4-bromo-2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
3- ((4- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
4-bromo-5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
8- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
4-bromo-5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydroquinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
5-bromo-6- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- ((2- ((4- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (3- (((2- ((4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methylmethanesulfonamide;
n- (1- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (1- (1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (2- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
4- ((1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
6- (6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
4'- ((4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
4'- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) propan-1-yl)
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
4- (4- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperidin-4-yl) (methyl) amino) methyl) isoindoline-1, 3-dione;
4-bromo-2- (2, 6-dioxopiperidin-3-yl) -6- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
4-bromo-6- ((4- (4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
n- ((4- (((2R) -4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl)]-2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
N- ((4- (((2R) -4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (6- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (8- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
N- ((4- (((2R) -4- (3- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] octane-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- ((1R, 4R) -5- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- ((1S, 4S) -5- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (5- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] octane-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
N- ((4- (((2R) -4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- (2- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) ethyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
3- (5- ((4- (1- (4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-yl) ethyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
n- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -4, 9-dioxo-4, 9-dihydronaphtho [2,3-b ] furan-2-carboxamide;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2-chlorophenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (3- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-chlorophenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((2S) -5-amino-1- (3- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-chlorophenoxy) -5-oxopent-2-yl) carbamoyl) -3-methyl-6-oxodecahydropyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) methyl) piperidin-4-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
((2- (((5S, 8S,10 ar) -8- (((S) -5-amino-1- (benzhydrylamino) -1, 5-dioxopent-2-yl) carbamoyl) -3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -6-oxodecahydro pyrrolo [1,2-a ] [1,5] diazocine-5-yl) carbamoyl) -1H-indol-5-yl) difluoromethyl) phosphonic acid;
3- (7-bromo-5- (((3- ((3 ar,4s,9 br) -4- (hydroxymethyl) -1- (pyridin-4-ylmethyl) -2, 3a,4,5,9 b-hexahydro-1H-pyrrolo [3,2-c ] quinolin-8-yl) phenyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
6- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
n- (4- (5- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -3- (tert-butyl) -1,2, 4-oxadiazole-5-carboxamide;
n- (4- (5- (4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -3- (tert-butyl) -1,2, 4-oxadiazole-5-carboxamide;
N- (4- (5- (4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) -1H-indazol-3-yl) -2-methylbenzyl) -3- (tert-butyl) -1,2, 4-oxadiazole-5-carboxamide;
3- (6-bromo-5- ((4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((3- (4- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperazin-1-yl) azetidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (((1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (1- (6- ((2 ' - (7, 7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta [4,5] pyrrolo [1,2-a ] pyrazin-2-yl) -3' - (hydroxymethyl) -1-methyl-6-oxo-1, 6-dihydro- [3,4' -bipyridin ] -5-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -7-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -7-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (((1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (1- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (((1- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((2- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenoxy) ethyl) (methyl) amino) methyl) -7-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (((1- (3- (2, 3-dichlorophenyl) -1H-pyrazolo [3,4-b ] pyrazin-6-yl) -4-methylpiperidin-4-yl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (6- (4-amino-4-methylpiperidin-1-yl) -1H-pyrazolo [3,4-b ] pyrazin-3-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) piperazin-1-yl) methyl) -7-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (3- (3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) -2-chlorophenyl) piperazin-1-yl) methyl) -4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((((3 s,4 s) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) amino) methyl) -6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3-amino-5- ((3 s,4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyridin-2-yl) piperazin-1-yl) methyl) -7-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -4-methylpiperidin-4-yl) amino) methyl) -4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((2, 3-difluoro-6- (2-morpholinothiazol-4-yl) phenoxy) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
6- (4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) pyridazin-3-carboxamide;
6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) nicotinamide;
6- (8- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (6- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (3- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-6-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
6- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) pyridazine-3-carboxamide;
3- (4-bromo-5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (7- (((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) amino) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
2- (6- (6- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -pyridazin-3-yl) -1-oxoisoindolin-2-yl) -2- (5-fluoro-2-hydroxyphenyl) -N- (thiazol-2-yl) acetamide;
3- (4-bromo-5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (((1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (1- (6- ((2- (1- (cyclopropylsulfonyl) -1H-pyrazol-4-yl) pyrimidin-4-yl) amino) -1-isopropyl-1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (1- (1-isopropyl-6- ((2- (4-methoxypiperidin-1-yl) pyrimidin-4-yl) amino) -1H-pyrazolo [4,3-c ] pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) piperidine-4-carboxamide;
1'- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) - [1,4' -bipiperidin ] -4-carboxamide;
4- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -N- (5- (((5- (tert-butyl) oxazol-2-yl) methyl) thio) thiazol-2-yl) piperazine-1-carboxamide;
N- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (2, 6-dichlorobenzoylamino) -1H-pyrazole-3-carboxamide;
1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -N- (5-chloro-4- (5, 5-dimethyl-5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazol-3-yl) pyridin-2-yl) piperidine-4-carboxamide;
2- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methoxy) phenyl) -N- (5-cyclobutyl-1H-pyrazol-3-yl) acetamide;
3- (4-bromo-5- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -N- (4- (((5- (((S) -1-hydroxybutan-2-yl) amino) -3-isopropylpyrazolo [1,5-a ] pyrimidin-7-yl) amino) methyl) phenyl) piperazine-1-carboxamide;
4- (((4- (2- ((1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) -5-chloropyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((2 ' - ((1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) amino) -5' -chloro- [2,4' -bipyridin ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
3- ((4- (2- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) -4-methylthiazol-5-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
2- ((6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide;
2- ((6- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide;
2- ((6- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide;
4- ((4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
4- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
n- (4- ((4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
n- (4- (4- (((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
2- (4- ((3S) -1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-3-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) -2H-indazole-7-carboxamide;
2- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -2H-indazole-7-carboxamide;
3- (4-bromo-5- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((4- (8-fluoro-1-oxo-2, 3,4, 6-tetrahydro-1H-azepin) o [5,4,3-cd ] indol-5-yl) benzyl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- ((5- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-2-yl) amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
2- ((5- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) pyridin-2-yl) amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
2- ((5- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) pyridin-2-yl) amino) -7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
3- (4-bromo-5- ((4- ((6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (difluoro (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- (((1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperazin-1-yl) methyl) -4-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) (methyl) amino) methyl) -6-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (6- ((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido [2,3-d ] pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -7-bromo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- ((4- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) -3-methoxyphenyl) amino) -6-ethyl-5- ((tetrahydro-2H-pyran-4-yl) amino) pyrazine-2-carboxamide;
3- (4-bromo-5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- ((4- (4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
8- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
8- (4- (((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
3- (4-bromo-5- ((4- (1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (1- (4- (5, 7-dimethoxy-4-oxo-3, 4-dihydro-quinazolin-2-yl) phenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
2- ((2- ((4- (4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (3- (((2- ((4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (3- (((2- ((4- (4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyridin-2-yl) -N-methyl methanesulfonamide;
n- (1- (1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
N- (1- (1- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- (2- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
4- ((1- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) ethynyl) -1- (((2 s,3s,4 s) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinoline-6-carboxamide;
6- (6- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
6- (6- (4- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -pyridin-3-yl) -1-isopropyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) -1H-indazole-4-carboxamide;
4'- ((4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) methyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
4'- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
4- (4- (((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
4- (4- (1- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
3- (4-bromo-5- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxo-isoindolin-2-yl) piperidine-2, 6-dione;
3- (4-bromo-5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-bromo-5- (((1- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-bromo-5- ((4- (4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
N- ((4- (((2R) -4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl-2,2,3,3,5,5,6,6-d) 8 ) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl)]-2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 6-dimethylpiperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (6- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
N- ((4- (((2R) -4- (3- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-6-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (8- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (3- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-8-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- ((1R, 4R) -5- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
N- ((4- (((2R) -4- ((1S, 4S) -5- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (5- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -2, 5-diazabicyclo [2.2.2] oct-2-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((4-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- ((4- (((2R) -4- (4- ((6-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
N- ((4- (((2R) -4- (4- ((7-bromo-2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -1- (phenylsulfanyl) butan-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) benzamide;
n- (5- (3, 5-dimethoxyphenethyl) -1H-pyrazol-3-yl) -4- ((3R, 5S) -4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 5-dimethylpiperazin-1-yl) benzamide;
3- (1-oxo-5- ((4- (4- (3- (quinolin-4-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
3- (1-oxo-5- ((4- (4- (3- (quinolin-5-yl) pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) piperazin-1-yl) methyl) isoindolin-2-yl) piperidine-2, 6-dione;
1'- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -6- (4-phenoxyphenyl) -1',2',3',6 '-tetrahydro- [2,4' -bipyridine ] -5-carboxamide;
6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) piperidin-1-yl) -2- (4-phenoxyphenyl) nicotinamide;
3- (5- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- (4-chloro-1, 2-diphenyl-but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4- ((((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide;
n- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
N- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) piperazin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
3- (4- ((4- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
8- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -9-ethyl-6, 6-dimethyl-11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (3- (((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
N- (3- (((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
n- (3- (((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) phenyl) -N-methyl methanesulfonamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -5-morpholinopyrazolo [1,5-a ] pyrimidine-3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4'- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl- [1,1' -biphenyl ] -3-carboxamide;
N- (5- (3, 5-difluorobenzyl) -1H-indazol-3-yl) -4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2- ((tetrahydro-2H-pyran-4-yl) amino) benzamide;
3- (5- ((4- ((4- (((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) amino) -7-methoxy-2-methyl quinazolin-6-yl) oxy) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (1- (6- ((5-fluoro-4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- (1, 2-bis (4-hydroxyphenyl) but-1-en-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((1 s,2 r) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- ((1 s,2 r) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- ((1 s,2 r) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- ((1 s,2 r) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((1 r,2 s) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((1 s,2 r) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((3R, 4S) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- ((3R, 4S) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- ((3R, 4S) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- ((3R, 4S) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((3 s,4 r) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((3R, 4S) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((1- (4- ((9-cyclopentyl-8- (phenylamino) -9H-purin-2-yl) amino) phenyl) piperidin-4-yl (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphonyl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphonyl) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (1- (4- ((5-bromo-4- ((5- (dimethylphosphono) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- ((5-chloro-4- (5- (cyclopropylmethyl) -1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
4- (((4- (5-chloro-2- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) amino) pyridin-4-yl) thiazol-2-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
4- (((5 ' -chloro-2 ' - ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) amino) - [2,4' -bipyridyl ] -6-yl) amino) methyl) tetrahydro-2H-pyran-4-carbonitrile;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
N- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b ] pyridazin-3-ylethynyl) -4-methylbenzamide;
3- (4- (((1- (4- ((5-chloro-4- ((2- (dimethylphosphonyl) phenyl) amino) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-4-yl) (methyl) amino) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- ((2- ((4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -piperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide;
n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide;
N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide;
n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide;
n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide;
n- (3- (((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) methyl) pyrazin-2-yl) -N-methylmethanesulfonamide;
3- (5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4-fluoro-5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (6-fluoro-5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (7-fluoro-5- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (4- ((4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
n- (2- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) -5- ((R) -3-hydroxypyrrolidin-1-yl) oxazolo [4,5-b ] pyridin-6-yl) -2- (2-methylpyridin-4-yl) oxazole-4-carboxamide;
3- (4- ((4- (6- (6- ((R) -2- (3-fluorophenyl) pyrrolidin-1-yl) imidazo [1,2-b ] pyridazin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((1 s,2 r) -6-hydroxy-2-phenyl-1, 2,3, 4-tetrahydronaphthalen-1-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
2- (2, 6-Dioxopiperidin-3-yl) -5- ((4- (4- ((3R, 4S) -7-hydroxy-3-phenylchroman-4-yl) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
5- ((4- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperazin-1-yl) methyl) -2- (2, 6-dioxo-3-yl) isoindoline-1, 3-dione;
5- (((1- (4- ((5-bromo-4- ((5- (dimethylphosphino) quinoxalin-6-yl) amino) pyrimidin-2-yl) amino) -5-methoxy-2-methylphenyl) piperidin-4-yl) (methyl) amino) methyl) -2- (2, 6-dioxo-3-yl) isoindoline-1, 3-dione;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
n- (4- (chlorodifluoromethoxy) phenyl) -6- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide;
2- ((2- ((4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
2- ((2- ((4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) -2-isopropoxy-5-methylphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -N-methylbenzamide;
n- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -2-fluoro-5-methoxy-4- ((4- ((2-methyl-3-oxoisoindolin-4-yl) oxy) -5- (trifluoromethyl) pyrimidin-2-yl) amino) benzamide;
2- (2, 6-dioxopiperidin-3-yl) -5- ((4- (4- ((3- (methylsulfonyl) phenylmethyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) isoindoline-1, 3-dione;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- ((1 r,4 r) -4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) carbamoyl) cyclohexyl) -4- (isopropylamino) nicotinamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-4-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
6- (5-cyano-1H-pyrrolo [2,3-b ] pyridin-1-yl) -N- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -4- (isopropylamino) nicotinamide;
2- (2- ((cyclopropylmethyl) amino) pyridin-4-yl) -N- (3- (difluoromethyl) -1- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) oxazole-4-carboxamide;
n- (3- (difluoromethyl) -1- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -1H-pyrazol-4-yl) -2- (2- ((2, 2-trifluoroethyl) amino) pyridin-4-yl) oxazole-4-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) azetidin-1-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide;
N- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylene) azetidin-1-yl) methyl) piperidin-1-yl) pyridazin-3-carboxamide;
n- ((1 r,4 r) -4- (3-chloro-4-cyanophenoxy) cyclohexyl) -6- (4- ((3- ((1S) - (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) (hydroxy) methyl) -3-hydroxyazetidin-1-yl) methyl) piperidin-1-yl) pyridazine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) piperidine-3-carboxamide;
n- ((1 r,3 r) -3- (3-chloro-4-cyanophenoxy) -2, 4-tetramethylcyclobutyl) -6- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methylene) azetidin-1-yl) methyl) piperidin-1-yl) piperidine-3-carboxamide;
7-cyclopentyl-2- ((5- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
7-cyclopentyl-2- ((5- (4- ((3- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxo-isoindolin-5-yl) methyl) azetidin-1-yl) methyl) piperidin-1-yl) pyridin-2-yl) amino) -N, N-dimethyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide;
N- (2-chloro-6-methylphenyl) -2- ((6- (4- ((4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide;
3- (5- ((4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) piperidin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (4- ((4- (((4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4,3-d ] pyrimidin-2-yl) oxy) methyl) piperidin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -4-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -6-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
3- (5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -7-fluoro-1-oxoisoindolin-2-yl) piperidine-2, 6-dione;
5- ((4- (6- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyridin-2-yl) piperazin-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) piperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- ((1 s,4 s) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- (((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) (methyl) amino) piperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 8-diazabicyclo [3.2.1] oct-3-yl) phenyl) -4-fluoro-1-oxoisoindolin-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) -3, 3-difluoropiperidin-4-yl) piperazin-1-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- ((1 r,4 r) -5- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindol-5-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
2- (6, 7-dihydro-5H-pyrrolo [1,2-c ] imidazol-1-yl) -2- (6- (4- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperazin-1-yl) -3, 3-difluoropiperidin-1-yl) phenyl) -4-fluoro-1-oxoisoindol-2-yl) -N- (thiazol-2-yl) acetamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -7-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] thiazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
N- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -5- (2-hydroxypropan-2-yl) benzo [ d ] oxazol-6-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -6- (2-hydroxypropan-2-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide;
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -4-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -6- (2-hydroxypropan-2-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide; and
n- (2- (1- ((2- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1-oxoisoindolin-5-yl) methyl) piperidin-4-yl) -6- (2-hydroxypropan-2-yl) -2H-indazol-5-yl) -6- (trifluoromethyl) pyridine-2-carboxamide.
31. A compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, polymorph thereof according to any one of claims 12 to 30, which is a hydrohalate (including hydrochloride, hydrobromide), sulphate, citrate, maleate, mesylate, citrate, lactate, L-tartrate, fumarate, L-malate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, mesylate, hippurate, glycolate or p-toluenesulfonate salt of the compound of formula (II).
32. A pharmaceutical composition comprising as active ingredient a compound of formula (I) as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, prodrug or polymorph thereof, and at least one pharmaceutically acceptable carrier.
33. The pharmaceutical composition of claim 32, further comprising at least one additional therapeutic agent, such as an anticancer agent.
34. A pharmaceutical composition comprising as active ingredient a compound of formula (II) as defined in any one of claims 12 to 30, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof, and at least one pharmaceutically acceptable carrier.
35. The pharmaceutical composition of claim 34, further comprising at least one additional therapeutic agent, such as an anticancer agent.
36. A kit or kit comprising:
a compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; or (b)
A compound of formula (II) as defined in any one of claims 12 to 30 or a pharmaceutically acceptable salt thereof; or (b)
The pharmaceutical composition of claim 32 or 34.
37. Use of a compound of formula (I) as defined in any one of claims 1 to 11 or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition mediated by cereblon.
38. The use of claim 37, wherein the cereblon protein-mediated disease or disorder comprises: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, weng Weili Hirudo syndrome, richter Syndrome (RS), acute liver failure and diabetes.
39. The use of claim 37, wherein the cereblon protein-mediated disease or disorder is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; glioma of brain; astrocytoma; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; glioma; peripheral nerve epithelial tumors; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor;
Esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer;
cancer of the head and neck; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; weng Weili Hirudt syndrome; richter Syndrome (RS); sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; autoinflammatory diseases including gout and the like; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; cardiovascular disease (including congestive heart failure, myocardial infarction, coronary heart disease, atherosclerosis); multiple organ failure due to cachexia and septic shock; and acute liver failure.
40. Use of a compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analog, prodrug or polymorph thereof according to any one of claims 12 to 30 for the preparation of a medicament for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of: tumors, infectious diseases, auto-inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anaemia, hemorrhagic shock, transplant rejection, multiple Organ Dysfunction Syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, cardiovascular diseases, weng Weili Hirsh syndrome, richter Syndrome (RS), acute liver failure, diabetes, kennedy disease (Kennedy disease), seborrheic alopecia, hirsutism, skin diseases, functional uterine bleeding, anaemia, pediatric aplastic anemia, endometriosis, transplant rejection, polycystic ovary syndrome, and thyroid diseases.
41. The use of claim 40, wherein the disease or condition is selected from the group consisting of: myeloma, including multiple myeloma, plasma cell myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); myelodysplastic syndrome treated in the past; transplantation-related cancers; neutropenia; leukemia, including acute myelogenous leukemia, chronic myelogenous leukemia, B-cell chronic lymphocytic leukemia, anemia associated with leukemia, acute Myelogenous Leukemia (AML); lymphomas including diffuse large B-cell lymphomas, non-hodgkin lymphomas, anaplastic large cell lymphomas, CD20 positive lymphomas, mantle cell lymphomas, primary lymphomas, B-cell lymphomas, recurrent B-cell non-hodgkin lymphomas, recurrent diffuse large B-cell lymphomas, recurrent mediastinal (thymus) large B-cell lymphomas, primary mediastinal (thymus) large B-cell lymphomas, recurrent transformed non-hodgkin lymphomas, refractory B-cell non-hodgkin lymphomas, refractory diffuse large B-cell lymphomas, refractory primary mediastinal (thymus) large B-cell lymphomas, refractory transformed non-hodgkin lymphomas; thyroid cancer; melanoma; lung cancer, including lung adenocarcinoma, lung squamous carcinoma, non-small cell lung cancer, and small cell lung cancer; inflammatory myofibroblastic tumor; colorectal cancer; intestinal cancer; glioma of brain; astrocytoma; glioma; peripheral nerve epithelial tumors; ovarian cancer; bronchial carcinoma; prostate cancer; breast cancer, including triple negative breast cancer, sporadic breast cancer and cowden patients; pancreatic cancer; central nervous system cancer; neuroblastoma; an extramedullary plasma cell tumor; plasmacytoma; stomach cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; uterine cancer; cancer of the head and neck; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various adipose-derived tumors, ewing's sarcoma/primitive neuroectodermal tumors (Ewing/PNETs), and leiomyosarcoma; urothelial cancer; basal cell carcinoma; squamous cell carcinoma of the oral cavity; bile duct cancer; bone cancer; cervical cancer; skin cancer; weng Weili Hirudt syndrome; richter Syndrome (RS); sepsis syndrome; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcer, kawasaki disease, polymyositis/dermatomyositis, sjogren's syndrome, atopic dermatitis; keratoconjunctival dryness; autoinflammatory diseases including gout and the like; inflammatory diseases including crohn's disease and ulcerative colitis, pneumonia, osteoarthritis, synovitis, systemic inflammatory response syndrome, airway inflammation, bronchitis; cerebral malaria; infectious diseases including viral pneumonia, AIDS, covd-19 novel coronavirus infection, gram negative bacterial infection, gram positive bacterial infection, tuberculosis, etc.; infectious shock; bacterial meningitis; chronic obstructive pulmonary disease; asthma; hemorrhagic shock; organ (including kidney, heart, lung) or tissue graft rejection; diabetes mellitus; sarcoidosis; adult respiratory distress syndrome; multiple organ failure due to cachexia and septic shock; acute liver failure; functional uterine bleeding; anemia; aplastic anemia of children; endometriosis; polycystic ovary syndrome; thyroid diseases; cardiovascular disease (e.g., coronary heart disease, congestive heart failure, myocardial infarction, atherosclerosis); skin diseases (e.g., acne); kennedy disease (Kennedy disease); seborrheic alopecia; and hirsutism.
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912655A (en) * | 2017-12-13 | 2019-06-21 | 上海科技大学 | Alk protein degradation agent and its antitumor application thereof |
| CN110240629A (en) * | 2018-03-09 | 2019-09-17 | 上海科技大学 | Protein degradation targets BCR-ABL compound and its antitumor application thereof |
| CN110267659A (en) * | 2016-12-08 | 2019-09-20 | 西奈山伊坎医学院 | For treating the composition and method of the cancer of CDK4/6 mediation |
| CN110506039A (en) * | 2016-10-11 | 2019-11-26 | 阿尔维纳斯股份有限公司 | Compounds and methods for for androgen receptor targeting degradation |
| CN110724143A (en) * | 2019-10-09 | 2020-01-24 | 清华大学 | Preparation of target BTK protein degradation compound and application of target BTK protein degradation compound in treatment of autoimmune system diseases and tumors |
| CN112079866A (en) * | 2019-06-12 | 2020-12-15 | 上海科技大学 | ALK protein regulator and anti-tumor application thereof |
| CN112105385A (en) * | 2017-12-26 | 2020-12-18 | 凯麦拉医疗公司 | IRAK degrading agents and uses thereof |
| WO2021036922A1 (en) * | 2019-08-23 | 2021-03-04 | 北京泰德制药股份有限公司 | Compound inhibiting and inducing degradation of egfr and alk |
| WO2021091575A1 (en) * | 2019-11-08 | 2021-05-14 | Nurix Therapeutics, Inc. | Bifunctional compounds for degrading btk via ubiquitin proteosome pathway |
| WO2021121261A1 (en) * | 2019-12-16 | 2021-06-24 | 北京泰德制药股份有限公司 | Compound for inhibiting and inducing degradation of egfr kinase |
| WO2021133886A1 (en) * | 2019-12-23 | 2021-07-01 | Accutar Biotechnology | Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer |
| CN113164409A (en) * | 2018-11-21 | 2021-07-23 | 冰洲石生物科技公司 | Novel compounds having estrogen receptor alpha-degrading activity and uses thereof |
| WO2021155050A1 (en) * | 2020-01-29 | 2021-08-05 | Biotheryx, Inc. | Kinase modulators, pharmaceutical compositions, and therapeutic applications |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL293481A (en) * | 2019-12-06 | 2022-08-01 | Celgene Corp | Processes for preparing 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
| CN114057770B (en) * | 2020-08-06 | 2023-05-02 | 成都先导药物开发股份有限公司 | Bifunctional compounds targeting EGFR protein degradation |
-
2022
- 2022-12-08 CN CN202211638397.8A patent/CN116239566A/en active Pending
- 2022-12-08 WO PCT/CN2022/137582 patent/WO2023104155A1/en active Application Filing
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- 2022-12-08 EP EP22903574.6A patent/EP4446324A1/en active Pending
- 2022-12-08 KR KR1020247022815A patent/KR20240148007A/en unknown
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110506039A (en) * | 2016-10-11 | 2019-11-26 | 阿尔维纳斯股份有限公司 | Compounds and methods for for androgen receptor targeting degradation |
| CN110267659A (en) * | 2016-12-08 | 2019-09-20 | 西奈山伊坎医学院 | For treating the composition and method of the cancer of CDK4/6 mediation |
| CN109912655A (en) * | 2017-12-13 | 2019-06-21 | 上海科技大学 | Alk protein degradation agent and its antitumor application thereof |
| CN112105385A (en) * | 2017-12-26 | 2020-12-18 | 凯麦拉医疗公司 | IRAK degrading agents and uses thereof |
| CN110240629A (en) * | 2018-03-09 | 2019-09-17 | 上海科技大学 | Protein degradation targets BCR-ABL compound and its antitumor application thereof |
| CN113164409A (en) * | 2018-11-21 | 2021-07-23 | 冰洲石生物科技公司 | Novel compounds having estrogen receptor alpha-degrading activity and uses thereof |
| CN112079866A (en) * | 2019-06-12 | 2020-12-15 | 上海科技大学 | ALK protein regulator and anti-tumor application thereof |
| WO2021036922A1 (en) * | 2019-08-23 | 2021-03-04 | 北京泰德制药股份有限公司 | Compound inhibiting and inducing degradation of egfr and alk |
| CN110724143A (en) * | 2019-10-09 | 2020-01-24 | 清华大学 | Preparation of target BTK protein degradation compound and application of target BTK protein degradation compound in treatment of autoimmune system diseases and tumors |
| WO2021091575A1 (en) * | 2019-11-08 | 2021-05-14 | Nurix Therapeutics, Inc. | Bifunctional compounds for degrading btk via ubiquitin proteosome pathway |
| WO2021121261A1 (en) * | 2019-12-16 | 2021-06-24 | 北京泰德制药股份有限公司 | Compound for inhibiting and inducing degradation of egfr kinase |
| WO2021133886A1 (en) * | 2019-12-23 | 2021-07-01 | Accutar Biotechnology | Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer |
| WO2021155050A1 (en) * | 2020-01-29 | 2021-08-05 | Biotheryx, Inc. | Kinase modulators, pharmaceutical compositions, and therapeutic applications |
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